2EPORT� Table of Contents

2EPORT Table of Contents

Boards ...... 5 Group Leaders - Core Sector ...... 6 Research Groups - Outer Circle ...... 8 Concept and Structure of the IZN ...... 13 IZN Budget and grant giving bodies ...... 19 Collaborations of IZN Members ...... 20 Research Profiles - Core Sector ...... 25 Hilmar Bading ...... 26 Roland Brandt ...... 28 Francesca Ciccolini ...... 30 Uwe Ernsberger ...... 32 Hans-Hermann Gerdes ...... 34 Siegfried Mense ...... 36 Hannah Monyer ...... 38 Andrei Rozov ...... 40 Horst Simon ...... 42 Jacqueline Trotter ...... 44 Kerry L. Tucker ...... 46 Klaus Unsicker ...... 48 William Wisden ...... 50 Research Profiles - Outer Circle ...... 53 Bernd W. Böttiger ...... 54 Andreas Draguhn ...... 55 Herta Flor ...... 56 Rainer Friedrich ...... 57 Harald Hutter ...... 58 Marika Kiessling ...... 59 Joachim Kirsch ...... 60 Ulrich Misgeld ...... 61 Stefan Offermanns ...... 62 G. Elisabeth Pollerberg ...... 63 Klaus Sartor ...... 64 Johannes Schröder ...... 65 Markus Schwaninger ...... 66 Peter H. Seeburg ...... 67 Jeremy C. Smith ...... 68 Rainer Spanagel ...... 69 Brigitte Wildemann ...... 70 Joachim Wittbrodt ...... 71 Central Facilities ...... 74 IZN Teaching Program ...... 76 Publications of IZN members, 2001-2002 ...... 87 Symposia and Seminars ...... 95 Guest Scientists 2001-2002 ...... 110 Diploma and Doctoral Theses ...... 111

Boards

Board of Directors

Hilmar Bading, Professor Dr.

Hannah Monyer, Professor Dr.

Klaus Unsicker, Professor Dr. (acting director)

Scientific Advisory Board

Prof. Dr. Adriano Aguzzi, Zürich

Prof. Yehezkel Ben-Ari, M.D, Ph.D., Marseille

Prof. Dr. Anders Björklund, Lund

Dr. Magdalena Götz, München

Prof. Nathaniel Heintz, Ph.D., New York

Prof. Dr. Arthur Konnerth, München

Prof. Mark Mattson, M.D., Ph.D., Baltimore

Prof. Dr. Hans-Christian Pape, Magdeburg

Prof. Mart Saarma, Ph.D., Helsinki

Prof. Stephen G. Waxman, M.D., Ph.D., New Haven

5 Group Leaders - Core Sector Group Leaders - Core Sector

Hilmar Bading, Professor Dr. Uwe Ernsberger, Privatdozent Dr. Development of nerve cells and generation of Neuronal calcium signaling neuronal diversity A +49-(0)6221-548218 A +49-(0)6221-548344 E +49-(0)6221-546700 E +49-(0)6221-545604 K [email protected] K [email protected]

Roland Brandt, Professor Dr. (until 11/02) Hans-Hermann Gerdes, Privatdozent Dr. Cytoskeletal mechanisms during neuronal devel- Membrane traffic in neuronal cell systems opment and degeneration A +49-(0)541-969 2338 A +49-(0)6221-548317 E +49-(0)541-969 2354 E +49-(0)6221-546700 K [email protected] K [email protected]

Roberto Bruzzone, Ph.D., INSERM guest group Dieter Langosch, Privatdozent Dr. (until 07/01) Assembly and function of membrane-embedded Cell communication by gap junction coupling protein domains A +49-(0)6221-562417 A +49-(0)8161-713500 E +49-(0)6221-561397 E +49-(0)-8161-714404 K [email protected] K [email protected]

Francesca Ciccolini, Ph.D. Siegfried Mense, Professor Dr. Peripheral and spinal mechanisms of muscle pain; Neural stem cell development and role of calcium neurotransmitters involved in the neuromodula- signaling in neural precursor differentiation tion of the reflex bladder A +49-(0)6221-548696 A +49-(0)6221-544193 E +49-(0)6221-546700 E +49-(0)6221-546071 K [email protected] K [email protected]

6 Group Leaders - Core Sector

Hannah Monyer, Professor Dr. Jacqueline Trotter, Ph.D. (until 03/03) Molecular cell biology of neuron-glia interaction Neuronal synchrony and plasticity and myelination A +49-(0)6221-562400 A +49-(0)6131-3922879 E +49-(0)6221-561397 E +49-(0)6131-3923840 K [email protected] K [email protected]

Anne Regnier-Vigouroux (until 12/00) Kerry Tucker, Ph.D. (as of 07/03) Control of peripheral nerve outgrowth in embry- Immune competence of astrocytes and microglia onic mouse development A +49-(0)6221 42 46 13 A +41-(0)61-697 5019 E +49-(0)6221 42 49 62 E +41-(0)61-697 3976 K [email protected] K [email protected]

Andrei Rozov, Dr. Klaus Unsicker, Professor Dr. TGF-ßs, FGFs and neurotrophins in neural deve- Mechanisms of short lasting synaptic plasticity lopment and functions A +49-(0)6221-562419 A +49-(0)6221-548227 E +49-(0)6221-541397 E +49-(0)6221-545604 K [email protected] K [email protected]

Horst Simon, Ph.D. William Wisden, Ph.D.

Development of midbrain dopaminergic neurons Inhibitory ion channels A +49-(0)6221-548342 A +49-(0)6221- 562403, -2411 E +49-(0)6221-545605 E +49-(0)6221-561397 K [email protected] K [email protected]

7 Research Groups - Outer Circle Research Groups - Outer Circle Department of Physiology and Pathophysiology Andreas Draguhn ZMBH Inhibitory synapses and network oscillations Konrad Beyreuther Alzheimer’s disease: etiology, physiological Wolfgang Kuschinsky and pathophysiological functions of APP and Proteomics and stroke presenilins Ulrich Misgeld Tobias Hartmann Plasticity of GABAA receptor mediated inhibi- Cellular regulation mechanisms of protein tion degradation and protein transport in Alz- heimer’s and Parkinson disease Horst Seller Autonomic control of cardiovascular functions Joachim Herz Lipids and their receptors in neurodegene- Department of Pharmacology rative diseases Rohini Kuner Molecular basis of chronic pain Renato Paro Chromatin and epigenetics, Alzheimer’s Dro- Stefan Offermanns sophila model Cellular signaling Blanche Schwappach Ta rgeting of ion channels Department of Human Genetics Gudrun Rappold Faculty of Biology Genetics of cognitive function and mental retardation G. Elisabeth Pollerberg Growth and orientation of axons during development of the vertebrate nervous system Department of Neuropathology Marika Kiessling Jeremy Smith Molecular basis of cerebral ischemia and Computer simulation of ion pumps ischemic preconditioning

Faculty of Medicine Heidelberg Neurology Dept. of Anatomy and Cell Biology Armin Grau Pathogenesis and genetics of stroke and Mul- Joachim Kirsch tiple Sclerosis Ontogeny, stabilization and functional adaptation of postsynaptic membrane specializa- Werner Hacke tions Molecular and cellular bases of stroke; stroke management

8 Research Groups - Outer Circle

Hans-Michael Meinck Psychiatry Movement disorders, channelopathies Johannes Schröder Functional neuroimaging correlates of neural Uta Meyding-Lamadé plasticity in age-associated neurocognitive Herpes simplex virus encephalitis disorders Markus Schwaninger Max-Planck Institute for Medical Research Molecular stroke research Michael Brecht Stefan Schwab/Thorsten Steiner Whisker representation Neuromonitoring and new concepts in stroke therapy Winfried Denk Development and application of new optical Klaus Sartor methods for biomedical research Focal cerebral ischemia, functional MR-tomography Thomas Euler Signal processing Michael Scherg/Andre Rupp Dynamic source imaging of the auditory cor- Dirk Feldmeyer tex with magnetoencephalography Functional and morphological aspects of synaptic interactions in defined neuronal circuits Brigitte Wildemann of the neocortex Peripheral immune tolerance and Multiple Sclerosis Rainer Friedrich Function and development of olfactory neural Anaesthesiology circuits Bernd W. Böttiger Harald Hutter Experimental cerebral ischemia Genetics of axon guidance in C. elegans Pediatrics Bert Sakmann Georg Hoffmann Mechanisms of fast signalling in and between Inherited (neuro-)metabolical diseases nerve cells, and of long-term changes in their synaptic coupling Dietz Rating Neurometabolical diseases, focal epilepsy, Peter Seeburg neurovegetative regulation in chronic pain The role of glutamate receptor subtypes in short and long-term memory

Veit Witzemann Molecular structure and function of the neuromuscular synapse during development

9 Research Groups - Outer Circle

German Cancer Research Center Neurology Medical Faculty Mannheim Christof Niehrs Achim Gass Embryonal cell fate during early vertebrate Contrast imaging for studying stroke and development Multiple Sclerosis

Heike Pöpperl Klaus Faßbender Hox genes in nervous system development Neuroimmunology

Günther Schütz Michael Daffertshofer Mechanisms of gene activation by extra-cellu- Clinical and experimental brain ischemia lar signals Michael Hennerici EMBL Molecular and cellular bases of stroke Mathias Treier Mammalian organogenesis and homeostasis

Jochen Wittbrodt Vertebrate retina development and differentiation

Central Institute for Mental Health (ZI) Mannheim Dusan Bartsch Molecular biology of normal and pathological learning and memory

Dieter Braus The influence of pharmacological treatment strategies on glutaminergic activity and neuro- plasticity in major psychiatric disorders

Herta Flor Learning and neuronal plasticity

Fritz Henn Neuroplastic changes in the development of depression and actions of antidepressant medications in reversing depression

Rainer Spanagel The neurobiology of drug dependence

10 Concept and Structure of the IZN

Concept and Structure of the IZN

Concept and Structure of the IZN European Molecular Biology Laboratory (EMBL) and the Mannheim Central Institute for Mental Health (ZI) occupy top rankings internationally. Publications in leading journals, external funding, and distinctions bestowed on outstanding Objectives personalities reflect the high-calibre and scientific standards The IZN has three objectives: of Heidelberg's neuroscience groups. Joint projects with the giant pharmaceutical and medium-sized biotechnology com- • "Bundling" of fundamental neuroscience research, to panies in the Heidelberg-Mannheim-Ludwigshafen region create synergies and increase refinement of scientific emphasize the links between basic and applied neuro- capacity sciences.

• intensify research in the fringe areas between basic and clinical neurosciences

• promote interactive research with the fields of physics, Brief history and structure of the IZN chemistry, mathematics and scientific computing The IZN was founded in 2000 and officially opened on June 16 in the presence of dignitaries representing the Baden- Württemberg Ministry for Science, Research, and Art, and Aims the University. The organizational form of the centre, approved by the Senate of the University and published as The main goal of the IZN is to promote the quality of sci- the Centre's Administration and Usage Regulations (Verwal- ence performed by its members, boost collaborations, pro- tungs- und Benutzungs-Ordnung, VBO), allows a group vide joint service units, and proceed towards integration of structure according to which both regular professors with basic and clinical neurosciences. Consistent application of tenure and scientists appointed on limited-term contracts the performance principle, regular external evaluation, early can act as group leaders. This structure guarantees scientific independence for promising scientists, performance-related continuity and allows constant innovation at the same time. distribution of resources, the establishment of a common infrastructure, and the establishment of an interdisciplinary IZN core sector postgraduate course of study in neurobiology are therefore The initial compound structure of the IZN was made up of essential aims of the IZN. three departments forming its "core sector", Neurobiology (Faculty of Biological Sciences), Clinical Neurobiology, and Neuroanatomy (Faculty of Medicine). Together with an Associate Professorship in Developmental Neuroscience, Neurosciences in Heidelberg which has been advertised, and an anticipated forth depart- Heidelberg is one of the strongholds of neuroscientific ment (Faculty of Biological Sciences), the "core sector" of research in Europe. Groups at the University and University the IZN is the basis for the desired interdisciplinary nature Hospital, the Max-Planck-Institute for Medical Research of the Centre. The core sector of the IZN currently com- (MPIMF), the German Cancer Research Centre (DKFZ), the 13 Concept and Structure of the IZN prises 12 independent research groups. Research group leaders are introduced in the research profiles (see pp 15).

IZN outer circle Selected groups working in neurosciences at both University and non-University institutions in Heidelberg and Mannheim together make up the outer circle. Members are outstanding neuroscience groups in the Medical Faculties of Heidelberg and Mannheim, in the Faculty for Biological Sciences, in the Max-Planck-Institute for Medical Research (MPIMF), in the German Cancer Research Center (DKFZ), and at the Euro- pean Molecular Biology Laboratories (EMBL). Members of the outer circle groups interact with the core groups in research, participate in graduate teaching, share central facilities of the core units, and provide methods and technolo- gies to the entire IZN: Membership of the outer circle is subject to the approval of the Advisory Board of the IZN. For a list of candidates, see pp. 8

Structure of the IZN

14 Concept and Structure of the IZN

Developments in the IZN since 2000 • Wieland Huttner was appointed as a director at the new Max-Planck-Institute of Molecular Cell Biology and Since its foundation in June 2000 the IZN has considerably Genetics in Dresden. changed and gained international visibility. Scientists at the IZN have been enormously successful with major discoveries • Dieter Langosch was appointed to a Professorship and in molecular, cellular, developmental, and systems neuro- Chair in Biophysics at the Technical University of science. Munich. • Hannah Monyer was appointed to a Schilling-Stiftung • Hilmar Bading was appointed as Professor and Chair of Professorship in Clinical Neurobiology and as Chair of Neurobiology and successor of Wieland Huttner. He the new Department of Clinical Neurobiology. She moved his group from Cambridge, UK, and has finished moved her group from the Max-Planck-Institute of Med- restructuring his facilities at buildings INF 364 and 345. ical Research to their new facilities in building INF 364. Soon after his arrival Hilmar received the Wolfgang Paul- She established a new Graduate College in Neurobio- Award of the Alexander von Humboldt Foundation, one logy, initiated, together with Peter Seeburg, the BMBF of the highest and most generously endowed awards in funded Heidelberg/Mannheim Genome Network in Neu- science. rosciences, and was instrumental in the reorganization • Michael Brand was appointed to a C3-equivalent posi- of the transgenic animal facility on campus. tion at the new Max-Planck-Institute of Molecular Cell • Andrei Rozov moved from the Max-Planck-Institute of Biology and Genetics in Dresden. Medical Research to the Department of Clinical Neuro- • Roland Brandt was appointed as Professor and Chair of biology and established his own group. Neurobiology at the University of Osnabrück, after • Elly Tanaka became a group leader at the Max-Planck- declining an offer to become a Professor of Molecular Institute of Molecular Cell Biology and Genetics in Neurology at the University of Bonn. Dresden. • Roberto Bruzzone moved his INSERM position from the • Jacqueline Trotter was appointed as Professor of Medi- Institut Pasteur to Heidelberg and established a guest cal Biology at the University of Mainz and is currently group in Clinical Neurobiology. moving her group. • Francesca Ciccolini moved from Cambridge, UK, and • Kerry Tucker, previously a postdoctoral fellow with established her own group in Neurobiology. Yves-Alain Barde in Munich and Basle, was granted an • Hans-Hermann Gerdes served as the acting head of independent research group by the German Research Neurobiology until Hilmar's arrival. He obtained second Foundation (DFG) within the Sonderforschungsbereich and third rankings on two lists for full professorships at 488. He will establish his group in building INF 345 the Universities of Osnabrück and Stuttgart, respec- starting on 1 July, 2003. tively. • Klaus Unsicker was awarded the Aschoff-Medal of the Medical Faculty of the University of Freiburg and contin-

15 Concept and Structure of the IZN

ued to serve as speaker of the Sonderforschungsbereich Heidelberg. Professor Flor has successfully installed her 488 and the DFG Research Group "Aminergic Systems". research group and initiated a DFG-funded Clinical Research Group on Pain. She is also the speaker of a • Bill Wisden pioneered the moves from Cambridge, UK, Sonderforschungsbereich Initiative "Learning, Memory, to Heidelberg. He became a group leader within the and Brain Plasticity. Implications for Psychopathology". Department of Clinical Neurobiology. • Christof Niehrs, DKFZ, was appointed to a Chair and We welcome all new group leaders and wish the leaving col- Professorship in Developmental Biology at the Faculty of leagues all the best with their new and challenging positions. Biology, after declining offers from the universities of Bochum and Karlsruhe. Christof received the prestigious Science Prize of the State of Baden-Württemberg in New Appointments to further consolidate the IZN 2001 and the Leibniz Prize of the German Research core sector Foundation in 2003. • Andreas Draguhn, formerly at the Physiology depart- • Stefan Offermanns was appointed to the Chair and Pro- ment of the Charité, Humboldt University Berlin, and fessorship in Molecular Pharmacology at the Medical Joachim Kirsch, former Chair and Professor of Anatomy Faculty. He contributed significantly to the reorganiza- and Cell Biology at the University of Ulm, have been tion of the transgenic animal facility. appointed as Professors and Chairs of Neurophysiology and Medical Cell Biology, respectively. Depending on • Renato Paro was appointed as C4-Professor in Molecu- the consent of the Scientific Advisory Board of the IZN, lar Biology at the ZMBH, University of Heidelberg, after the group leaders of the IZN have unanimously agreed declining offers of professorships in Mainz and Karls- to incorporate the research groups of Andreas Dra- ruhe. guhn, Joachim Kirsch, and Ulrich Misgeld, Professor of Physiology, into the core sector of the IZN.

New Appointments to the IZN outer circle Recent appointments made to the IZN outer circle include the following:

• Dusan Bartsch, former member of the Kandel laboratory at Columbia University, New York, was appointed as Professor of Molecular Neuroscience at the Central Institute for Mental Health (ZI) Mannheim.

• Herta Flor, former Chair in Psychology at the Humboldt- University Berlin, was appointed to a Chair and Profes- sorship in Neuropsychology at the ZI and University of

16 Concept and Structure of the IZN

Recent developments at the University of of Biological Sciences and Medicine have been instrumental Heidelberg with an impact on the IZN in the re-organization of the new facility for transgenic animals. Dr. J. Weiss, former director of the ZMBH transgenic Funding instruments facility, has been appointed as the new director. The facility The Sonderforschungsbereich 488 "Molecular and cellular is of utmost importance to the IZN to build up and maintain bases of neural development" was reviewed for its second the highest standards in transgenic animal research. funding period (2003-2005) and passed the Bewilligungs- ausschuss of the DFG. A new SFB initiative "Learning, Mem- ory, and Brain Plasticity" has been submitted to the DFG. In New laboratories for IZN junior groups in building addition to the already existing DFG Research and Clinical INF 345 Research Groups ("Aminergic Systems", "Pain"), new initia- Two stories in building INF 345 have been completely rebuilt tives for DFG-funded Research Groups in the areas of and will accomodate, amongst others, several junior groups "White Matter", "Cerebral Ischemia", and "Pain" have been of the IZN. launched.

The largest funding instruments with participation of the Heidelberg neuroscience community provided by the Federal Anticipated future developments in the IZN Ministry for Education and Science (BMBF) include the national Genome/NeuroNet, BioFuture, and MedNet Expected new appointments Ischemia projects. • Joachim Herz, Dallas, is currently negotiating for a Pro- fessorship in Molecular Biology at the ZMBH.

• Walter Rosenthal, Berlin, is negotiating for a Chair and BIOQUANT Professorship in Pharmacology, Medical Faculty. Members of the IZN and SFB 488 have been part of the suc- • A C3-Professorship in Developmental Neurobiology in cessful initiative to establish a new research concept in the Faculty of Biological Sciences has been advertised. quantitative, physics- and mathematics-oriented biology (BIOQUANT). A new buildung on the INF campus will accomodate three C4-groups and numerous infrastructure and Funds and positions for the IZN junior groups from biophysics, computer simulation and modeling, molecular cell biology, infectiology, and neurobio- At present, the IZN has no central funds and almost no central positions from the University other than what the three logy. departments of the IZN core sector have contributed at the time when the IZN was founded. One position for an admin- strator is jointly financed by the University and the Medical New transgenic animal facility Faculty for a period of two years. The subsequent status of Members of the SFB 488 and IZN (H. Monyer, S. Offer- this position is uncertain. The lack of an IZN central fund manns, P. Seeburg) supported by the Deans of the Faculties means that the establishment and equipment of new junior

17 Concept and Structure of the IZN groups, service units, and even of professorships must be financed through the funds and positions of the three core departments. This is an entirely unacceptable situation, and we shall ask the Scientific Advisory Board to support the IZN's initiative to establish central funds for the IZN.

IZN central building At present, the departments of the IZN core sector including those that we expect to join the IZN soon, the IZN junior groups, and the service units of the IZN are housed in four different buildings dispersed over the entire INF campus. This situation is entirely unsatisfactory, does not favor scientific interactions, and is uneconomical, since it requires duplicating essential equipment in different locations. More- over, the IZN lacks a seminar room of adequate size. Previ- ous plans to make building INF 364 entirely available to the IZN have not been realized as yet. Therefore, an IZN central building is an important request for the near future.

18 IZN Budget and grant giving bodies

IZN Budget and grant giving bodies • Nachlass Herbert Dauss sowie Stiftung für Krebs- und Scharlachforschung The three departments of the IZN core sector are financed by basic funding (Grundausstattung, GA) of the University • Konrad Adenauer Stiftung and University Clinic, and by grants (Ergänzungsausstattung, • Allergan, Bayer AG, BASF, Biopharm, Boehringer Ingel- EA) from: heim, Leica, Merck Sharpe and Dohme, Novartis Pharma AG, SIRS-Lab, Steigerwald, Till Photonics • DFG

• BMBF The amount and distribution of these funds (in k EUR) for • Alexander von Humboldt Foundation the years 2001-2002 are shown in the table below:

• Volkswagen-Stiftung Department GA EA Ratio EA/ GA • Schilling-Stiftung Neurobiology 117 8 , 0 2616,8 2,22 • Hertie-Stiftung Clin. Neurobiology 698,7 2039,8 2,92 Neuroanatomy 2159 , 4 3874,2 1,79 • Stiftung Verum Total, core depts.: 4036,1 8530,8 2,31 • Fonds der Chemischen Industrie

• Alzheimer Forschung Initiative e.V. Personnel is financed as follows: • Deutsches Krebsforschungszentrum, Tumorzentrum, Heidelberg GA EA Ratio EA/ • EC GA Scientists 23 44 1,91 • Human Frontier Science Program Organization Students 3 3 1,00 Technicians 26 13 0,50 • Landesforschungsschwerpunkt Baden-Württemberg

• Landesgraduiertenkolleg

• Medizinische Fakultät Heidelberg The tables show clearly that the majority of the funding of • Kooperationsprojekt Forschungsförderung der the three departments of the „core sector“ comes from the Medizinischen Fakultät „Ergänzungsausstattung“.

• Studienstiftung des Deutschen Volkes

• Forskerakademiet Danmark

• Wilhelm Sander Stiftung

19 Collaborations of IZN Members

Collaborations of IZN Members Country Laboratory Name Project Title Germany, IZN, Neuro- Katrin Huber Cholinergic differentia- Internal cooperations within the IZN are indicated by dark background. Heidelberg anatomy, Unsicker tion in ret mutants group Country Laboratory Name Project Title Germany, IZN, Neuro- Lavinia Bhatt Synaptotagmin Hilmar Bading Heidelberg anatomy, Simon expression in sympa- group thetic ganglia Germany, DKFZ Günther Schütz Nuclear signaling and Germany, IZN, Clinical Neuro- Jakob von ChAT expression in Heidelberg network plasticity in Heidelberg biology, Monyer Engelhardt mouse brain neurons from CREB group knock-out mice Germany, MPI Hirnforschung H. Rohrer RCAS infection Planned: Frankfurt Germany, IZN, Neurobiology Ciccolini Group Nuclear calcium signa- France, ENS C. Goridis Phox2b mutant mice Heidelberg ling in stem cell diffe- Paris rentiation UK, King’s College P. J . M a s o n c-ret overexpression Germany, Max Planck Insti- Feldmeyer Paired recordings of London Heidelberg tute for Medical Group cultured hippocampal UK, University College M. Koltzenburg Neuron differentiation Research neurons London markers Germany, Max Planck Insti- Friedrich Group Nuclear calcium signa- USA, University of Miami J. Bixby Synaptotagmin Heidelberg tute for Medical ling in the zebra fish Miami expression Research olfactory bulb Hans-Hermann Gerdes Francesca Ciccolini Germany, IZN, Clinical Neuro- B. Wisden GABA receptor Germany, IZN, Neurobiology Hilmar Bading Role of nuclear calcium Heidelberg biology trafficking Heidelberg signalling in neural stem cell differentia- Germany, IZN, Neuroanatomy K. Unsicker Sorting of TGF beta 2 Heidelberg tion Germany, IZN, MPIMF P. Seeburg, GABA receptor Germany, IZN, SFB 488 Kerry Tucker In vitro development Heidelberg G. Köhr trafficking Heidelberg of neurospheres from a GFP-expressing mouse Germany, Institute for Human K. Kutsche Functional Genomics Hamburg- Genetics Roland Brandt Eppendorf Universitätsklinikum Germany, University of Frank- Volkmar Hans NF-M Glycosylation Germany, Institute of Cell S. Kuznetsov Regulation of myosin Frankfurt furt (Wiestler lab) Rostock Biology and Biosys- Va activity USA, University of Texas Estelle Sontag Ta u P h o s p h atase Inter- tems Technology Texas Southwestern action Austria, Institute of Molecu- G. Kreil, Trafficking of Medical Center Salzburg lar Biology, Austrian G. Lepperdinger Hyaluronsäure- USA, University of Albrecht Cle- NF-M Glycosylation Academy of synthase San Diego California ment (Cleve- Sciences land lab) USA NIH J. Hammer Role of myosin Va in Uwe Ernsberger secretory granule transport Germany, IZN, Heidelberg Unsicker, Huber Sympathoadrenal Heidelberg lineage Belgium, Dept. for Human J. Creemers Trafficking of furin Germany, IZN, Neuro- Lorena Esposito Neuronal markers in Leuven Genetics endoprotease Heidelberg anatomy, Unsicker adrenal chromaffin Switzer- Institut de Biologie R. Regazzi Role of Rab protein group cells land, Cellulaire et de trafficking of secretory Lausanne Morphologie granules Germany, IZN, Neuro- Katrin Huber Adrenal differentiation Heidelberg anatomy, Unsicker in Phox2b mutants University of Lausanne group

20 Collaborations of IZN Members

Country Laboratory Name Project Title Country Laboratory Name Project Title Norway, Div. Molecular Cell O. Bakke Involvement of adap- Germany, IZN, Clinical Neuro- Bill Wisden Mice with altered Oslo Biology, Dept. of tor proteins in Heidelberg biology, University GABA receptors in par- Biology, Univ. Oslo polarized secretion of Heidelberg valbumin-positive cells Austria, Brain Research W. Sieghart GABA receptor Germany, IZN, Clinical Neuro- Bill Wisden AMPA receptor KO in Vienna Institute trafficking Heidelberg biology, University cerebellar granule cells UK, Laboratory S. Tooze Secretory granule of Heidelberg London Secretory Pathways maturation Germany, IZN, Clinical Neuro- Andrei Rozov Functional characteri- Laboratory Heidelberg biology, University zation of in vivo Cancer Research of Heidelberg labeled GABA-ergic UK London interneurones Research Institute USA, SUNY Health Sci- Roger Traub The role of AMPA Siegfried Mense New York ence Center, receptors in GABAergic Brooklyn interneurones for net- Germany, Central Institute for H. Flor Cortical imaging work synchronicity Mannheim Mental Health during experimental muscle pain UK, School of Biomedi- Miles The role of AMPA Leeds cal Sciences, Uni- Whittington receptors in GABAergic Germany, Otto-Selz-Institut P. H ö l z l Arginine for treatment versity of Leeds interneurones for net- Mannheim of pain work synchronicity Germany, Urologische Klinik, K.-P- Jünemann Mechanisms of sacral UK, School of Biomedi- Eberhard Buhl The role of AMPA Kiel Universität Kiel neuromodulation Leeds cal Sciences, Uni- receptors in GABAergic Germany, Friedrich-Baur-Insti- D. Pongratz Morphology of myo- versity of Leeds interneurones for net- München tut, Universitäts- fascial trigger points work synchronicity klinik München Nether- Institute of Neuro- Hans van Hooft Characterization of a Germany, Dept. Pharmacol., T. Unger Receptor molecules on lands, biology, University subclass of hippocam- Berlin Charité, University muscle nociceptors Amster- of Amsterdam pal interneurones Berlin dam Denmark, Institute of Sen- L. Arendt- Non-nociceptive sen- Germany, Anatomical Insti- Michael Molecular and func- Aalborg sory Motor Interac- Nielsen sations from skeletal Freiburg tute, University of Frotscher tional characterization tion, Aalborg Univ. muscle Freiburg of ChAT positive Norway, Dept. Physiology, K. Hole Spinal mechanisms of interneurones in the Bergen Bergen University muscle pain hippocampus Canada, Dept. Physiology, B. Sessle Skeletal muscle as a USA, Dept. Neuro- Alexander Slow wave activity in Toronto Toronto University source of temporo- New York science, Albert Ein- Peinado postnatal cortex in gap mandibular pain stein College of junction KO mice USA, Dept. Physical Med. D.G. Simons Mechanisms of trigger Medicine Atlanta & Rehab., Emory point formation UK, Dept. Neuro- Richard Morris Postdoc exchange to University, Atlanta Edinburgh science, University analyse transgenic Hannah Monyer of Edinburgh mice generated in our lab Germany, Max Planck Insti- Peter Seeburg Mice with regulated France, Pasteur Institute Roberto Visiting scientist; func- Heidelberg tute for Medical ablation of the NR1b Research subunit Paris Bruzzone tional characterization of recombinant Pan- Germany, Max Planck Insti- Peter Seeburg Generation of trans- nexins Heidelberg tute for Medical genic mice with altered Research C-termini in the NR2A Andrei Rozov and 2B subunit Germany, MPI for Medical P. H . S e e b u r g Analysis of transgenic Heidelberg Research mice with genetically modified glutamate receptors 21 Collaborations of IZN Members

Country Laboratory Name Project Title Country Laboratory Name Project Title Germany, MPI for Medical B. Sakmann Mechanisms of LTP- USA, Department of Michael Cleary Pbx1 and midbrain Heidelberg Research induction Stanford Pathology dopaminergic neurons Germany, Dept. of Clinical H. Monyer Functional characteri- Stanford University Heidelberg Neurobiology Uni- zation of in vivo School of Medicine versity Hospital for labeled GABA-ergic Canada, Department of Psy- Richard Dyck Behavioral deficits in Neurology interneurones Calgary chology, Faculty of brain specific ErbB4 USA, Dept. of Neurobio- L.P. Wollmuth Multivesical release in Social Science mutant mice New York logy and Behavior neocortical excitatory Department of State University of synapses Neuroscience, Fac- New York at Stony ulty of Medicine Brook Germany, MPI of Neuro- Rüdiger Klein ErbB4 and the mid- Nether- Dept. of Experimen- N. Burnashev Postsynaptic mecha- Martins- biology brain dopaminergic lands, tal Neurophysio- nisms of LTP ried Department of neurons Amster- logy Vrije University Molecular Neuro- dam Amsterdam biology UK, School of Biomedi- M. Whittington Generation of theta Canada, Neuroscience Cairine Logan Engrailed dependent Leeds cal Sciences, Uni- frequency oscillations Calgary Research Group survival of midbrain versity of Leeds in neocortical net- Dept. of Cell Bio- dopaminergic neurons works logy and Anatomy University of Cal- Horst Simon gary Germany, IZN, Neuroanatomy Klaus Unsicker Quantitative determi- Jacqueline Trotter Heidelberg nations of dopamine in the nigrostriatal sys- USA SUNY J. Levine Joint paper tem Germany, MPI C. Linington See above Germany, IZN, Neuroanatomy Uwe Ernsberger Synaptotagmin Martins- Heidelberg expression in sympa- ried thetic ganglia Germany, MPI K.A. Nave Joint papers Germany, Physiology and Ulrich Misgeld KATP-channel activity Göttingen Heidelberg Pathophysiology in midbrain dopami- Germany, Max Delbrück Cen- F. Kirchhoff, Joint papers nergic neurons Berlin trum Berlin H. Kettenmann Germany, DKFZ Günther Schütz Microarray analysis of Germany, University Düssel- H.W. Müller Joint paper Heidelberg inductible dopami- Düsseldorf dorf nergic cell lines Germany, University Düssel- H.P. Hartung Joint paper USA Department of Joseph Bryan Sur1 and the mainte- Düsseldorf dorf Molecular and Cel- nance of midbrain Kerry L. Tucker lular Biology dopaminergic neurons Baylor College of Germany, IZN, Neurobiology Francesca In vitro development Medicine Heidelberg Ciccolini of neurospheres from a GFP-expressing mouse Sweden, Ludwig Institute for Thomas Nurr1 and the Stockholm Cancer Research Perlmann dopaminergic projec- Germany, Magdalena Goetz, Paolo Malatesta FACS sorting of neu- Karolinska Institute tion to the basal gan- Martins- Max Planck Insti- rons using GFP as a glia ried tute for Neurobiol- marker ogy USA Department of Klaus Kästner Role of HNF3a in Genetics postnatal midbrain Germany, Oliver Bruestle, Marius Wernig Use of GFP-labelled ES University of Penn- dopaminergic neurons Bonn University Bonn cells to repair sylvania Medical damaged brain tissue School

22 Collaborations of IZN Members

Country Laboratory Name Project Title Country Laboratory Name Project Title USA, New Albany Medical Frank Rice Mystacial pad innerva- Israel, Developmental Chaya Kalcheim Development of the York College tion in tau knock-out Jerusalem Biology, Hebrew SA cell lineage mice Univ. Med. School USA, New Peter Davies, Albert Cathy Andorfer New mouse models of Israel, Anatomy & Cell Avihu Klar TGF-ß, axonal growth York Einstein Medical Alzheimer's disease Jerusalem Biol., Hebrew Univ. and guidance College Med. School Germany, Goethe University Thomas Deller Lesion-induced reor- Finland, Biocenter Univ. Hel- Urs Arumäe, Receptors for GDNF Frankfurt ganization of the Helsinki sinki Mart Saarma family members hippocampus Ireland, Anatomy, Univ. Cork Ann Sullivan GDF-15 as a neuro- Sweden, Patrik Ernfors, Karo- Christel Baudet GDNF and nerve out- Cork trophic factor Stockholm linska Institute growth USA, Wake Dept. Neurobiol- Ron Oppen- TGF-ß and neuron Switzer- Friedrich Miescher Jean-Francois Genomic imprinting Forest ogy & Anatomy heim death land, Basel Institute Spetz and brain development France, INSERM Marseille Chris Hender- LIFRß ligands and pre- USA, Univ. of Massachu- Athena Functional analysis of Marseille son ganglionic sympathetic Waltham setts Med. School Andreadis the tau gene promoter neurons USA, Ohio State Univer- Lyn Jakeman Repair of injured spinal Australia Immunology, Univ. Sam Breit GDF-15 Columbus sity cord New South Wales Klaus Unsicker Italy, EMBL Liliana trkB, trkC mouse Montero- Minichiello mutants Germany, IZN, Neuroanatomy Uwe Ernsberger SA cell lineage tondo Heidelberg USA, Columbia University LLoyd Greene Genes specifically Germany, IZN, Clinical Neuro- Hannah Monyer Gap junction commu- New York regulated in chromaffin Heidelberg biology nication in FGF mutant development mice USA, Duke University Keith Parker SF1 knockout Germany, Institute for Ulrich Misgeld Growth factors regu- Chapel Hill Heidelberg Physiology and lating the developmen- Pathophysiology tal switch in GABA USA, Northwestern Jack Kessler Genes regulated in signaling Chicago University chromaffin cell development Germany, Institute for Phar- Stefan Neural crest develop- Heidelberg macology Offermanns ment in mice with USA, San UCSF Gail Martin FGF5 knockout mutations in G-pro- Francisco tein signaling Nether- Dev. Biol. Rosana Dono, FGF2 knockout Germany, Neurology Markus Roles of endogenous lands, Rolf Zeller Heidelberg Schwaninger FGF and other growth Utrecht factors in ischemia Germany, Neuroanatomy, Uni- Kerstin TGF-β/GDNF syn- β Germany, DKFZ Günther Schütz GR and CREB signaling Göttingen versity of Göttingen Krieglstein ergy, TGF- mouse Heidelberg in the development of mutants the SA cell lineage Bill Wisden Germany, DKFZ Christof Niehrs Cloning of a receptor Germany, IZN, Institute for J. Kirsch Planned work on role Heidelberg for GDF-15 Heidelberg Anatomy and Cell of gephyrin at devel- Germany, Central Institute for Rainer Spanagel Behavioral alterations Biology oping synapses Mannheim Mental Health, in mice with trkB/trkC Germany, Physiology A. Draguhn Planned work on Dept. Psycho- haploinsufficiencies Heidelberg electrophysiology on pharmacology transgenic mice over- USA, Chemoprevention, Anita Roberts, TGF-ß in the nervous expressing GABA-C Bethesda NIH, NCI Kathy Flanders system receptors

23 Collaborations of IZN Members

Country Laboratory Name Project Title Germany, MPI for Medical P. S e e b u r g Ongoing. Cerebellar Heidelberg Research granule cell-specific knockout of the NMDA receptor NR1 subunit gene Germany, Central Institute for R. Spanagel Planned work on Mannheim Mental Health, behavioural characteri- Dept. Psychophar- zation of mouse macology mutants lacking functional potassium channel and neurotransmitter receptor genes in cerebellum Germany, IZN, Clinical Neuro- H. Monyer Two projects ongoing. Heidelberg biology Cerebellar granule cell- specific knockout of AMPA receptor GluR-D subunit. Developing transgenic techniques for reversible modulation of neurons. UK, MRC Oxford Peter Somogyi Reversibly modulating Oxford neural activity: electrophysiology Finland, University of Esa Korpi Reversibly modulating Helsinki Helsinki neural activity. Animal behaviour Austria, University of Vienna Werner Reversibly modulating Vienna Sieghart neural activity: pharmacology UK, Dept. Pharma- Mark Farrant/ Granule cell London cology, University Stuart Cull- physiology: College Candy GABA-A receptors UK, Imperial College Stephen Brick- Granule cell London ley physiology: Potassium channels UK, MRC LMCB, Univer- Stephen Moss GABA-C receptors in London sity College brain

24 Research Profiles Research Profiles - Core Sector Research Profiles Nuclear calcium signaling and survival. For synapse-to- nucleus communication, neu- Hilmar Bading rons exploit the spatial and temporal diversity of calcium MD 1984 University of Heidelberg transients associated with Postdoctoral work at the Max-Planck Institut für Molkulare Genetik, electrical activation. Induc- Berlin, and at Harvard Medical School, Boston, USA tion of transcription and the Group leader at the MRC Laboratory of Molecular Biology, Cambridge, biological responses of neu- UK, 1993-2001, rons depend on how calcium Professor of Neurobiology, IZN, since 2001. enters the neurons, the amplitude of the signal, how Current Research long it lasts and what subcellular compartment it invades. Spatial calcium signaling The decoding, by transcriptional regulators, of information Neuronal activity-induced changes in the intracellular cal- contained in a given calcium transient provides a mechanism cium concentration control many processes in the develop- through which neuronal impulse patterns specify gene ing and the adult nervous system. Calcium is required for induction. However, it remains to be established exactly what neurotransmitter release and activates mechanisms that type of calcium signal is needed for activity-dependent neu- affect synaptic connectivity, promote survival, or cause cell ronal processes. Our central hypothesis is that increases in death. Calcium also signals to the nucleus to induce gene the nuclear calcium concentration, evoked by synaptic activ- expression, which may be relevant for long-lasting plasticity ity, are key regulators of long-lasting, gene expression- dependent plasticity and neuronal survival.

Opposing functions of synaptic and extrasynaptic NMDA receptors A second aspect of spatial calcium signaling is the localization of the calcium entry channel, in particular that of the N- Methyl-D-Aspartate (NMDA) type of glutamate receptor. Calcium entry through synaptic NMDA receptors stimulates the transcription-regulating complex CREB/CBP, induces brain-derived neurotrophic factor (BDNF) gene expression, and enhances neuronal survival. In striking contrast, extrasynaptic NMDA receptors couple to CREB shut-off and cell death pathways. Thus, the decision of whether a neuron sur- vives (and perhaps undergoes plasticity) or dies after glutamate exposure is dependent on the localization of the NMDA receptor activated. This concept of differential signaling by synaptic and extrasynaptic NMDA receptors has wide-ranging implications in particular for the understanding and treatment of neuro-pathological conditions such as stroke in which brain damage may be caused by the stimula- Fig. 1: Schematic illustration of differential signaling by synaptic and tion of extrasynaptic NMDA receptors. extrasynaptic NMDA receptors.

26 Hilmar Bading

Future Projects and Goals Selected Publications One objective of our future research program is to analyse [1] Chawla, S., et al. (1998) the relationship between synaptic stimuli, spatial calcium Science 281, 1505-1509. signaling, and activation of gene expression. Based on mech- [2] Bading, H. (2000) anistic insight into transcription regulation and information Eur. J. Biochem. 267, 5280-5283. on the nature of calcium signals and candidate target genes, [3] Hardingham, G.E, et al. (2001) Nature Neuroscience 4, 261-267. we will develop tools to selectively generate or interfere with [4] Hardingham, G.E, et al. (2002) calcium-regulated nuclear events. Their effects on neuronal Nature Neuroscience 5, 405-415. plasticity will be tested using multi-electrode array (MEA) [5] Hardingham, G.E. and Bading, H. (2003) technology; MEAs allow us to record firing patterns of Trends in Neurosci. 26, 81-89 groups of hippocampal neurons and to monitor signal- induced changes in network behaviour. A second goal is to Structure of the group investigate the coupling of extrasynaptic NMDA receptors to cell death pathways and to determine the role of nuclear cal- Group leader Hilmar Bading cium signaling in synaptic NMDA receptor-induced survival Postdoctoral fellows Otto Bräunling, programs. Peter Vanhoutte Engineer Anja Eder Graduate student Malte Wittmann Undergrad. student Jan-Marek Weislogel Technicians Iris Bünzli-Ehret Andrea Hellwig Ruth Jelinek Ursula Weiss

Contact Prof. Dr. Hilmar Bading IZN, Neurobiologie Universität Heidelberg Im Neuenheimer Feld 364 Fig. 2: Expression of an EYFP-coupled, membrane bound blocker of 69120 Heidelberg calcium/calmodulin in hippocampal neurons. Germany A +49-(0)6221 – 54 8218 E +49-(0)6221 – 54 6700 K [email protected]

27 Research Profiles Cytoskeletal mechanisms during ease-like hyperphosphorylation, during neuronal development and neurodegeneration. In degeneration another project, a panel of new monoclonal antibodies Roland Brandt has been generated against a fraction enriched for innerpe- Diploma (Biochemistry) 1988 University of Tübingen ripheral membrane proteins Master (Philosophy) 1990 Free University of Berlin [2] and characterized in Ph.D. 1990 Free University of Berlin order to analyze the role of 1990-1994 Postdoctoral work at the Center for Neurologic Diseases, selected components of the Harvard Medical School, Boston neuronal cytoskeleton dur- 1994-2002 Independent Group Leader at the Department of ing development and neuro- Neurobiology, IZN, University of Heidelberg degenerative processes. Since 2002 Full Professor of Neurobiology and Head of Department at the University of Osnabrück Future Projects and Goals We have recently shown that tau constructs that simulate a Current Research disease-like hyperphosphorylation induce neurodegenera- Neurons are one of the most extreme cell types in that they tive mechanisms in dissociated neurons that are associated contain processes which can reach a meter or longer and with apoptotic processes [5]. A major focus of our work contain more than 99% of the cellular volume [4]. This concentrates on (a) identifying the molecular mechanisms requires the presence of a sophisticated molecular machin- and the potential interference with other disease-relevant ery in order to establish and maintain such a morphology. The cytoskeleton is the major intraneuronal structure that determines the shape of a neuron. From that it is not sur- prising that cytoskeletal mechanisms have an important role during the development of neurons and that abnormalities in the cytoskeletal organization are a hallmark of many neurodegenerative diseases. The group concentrates on the function of microtubules and their associated proteins, on neurofilaments and on the membrane cortex during neuronal development and neurodegeneration. In particular, a major part of the group concentrates on studying the involvement of the neuronal microtubule-associated protein tau during neurodegenerative processes in Alzheimer's disease and other tauopathies. In the past years, effective gene-transfer techniques based on several viral vectors (HSV, Sindbis virus) have been established in the lab as a tool to express wildtype and disease-like modified tau constructs ("pseudo- hyperphosphorylated tau" [3, 5]) in dissociated neurons Schematic representation of the mechanism how modifications of tau and organotypic brain cultures. These techniques are used protein may contribute to the pathology of Alzheimer's disease (for de- to analyze the role of tau modifications, in particular a dis- tails see Shahani & Brandt, 2002)

28 Roland Brandt factors during tau-induced neurodegeneration, and (b) developing complex culture and animal models that could serve as models for tau pathologies.

In additional projects we will use our new antibodies to better understand the role of individual cytoskeletal components during neuronal development. This includes (a) use of an antibody that detects the protein gravin, a human kinase- anchoring protein that associates with the actin cortex of neurons and may be involved in localizing kinases to selected regions of developing neurites and (b) analysis of O-glycosylation of neurofilaments during neuronal development and degeneration with a novel antibody that specifically detects an O-glycosylated epitope in NF-M.

Selected Publications

[1] Fanara, P., et al. (1999) EMBO J. 18, 565-577. [2] Maas, T., et al. (2000) J. Biol. Chem. 275, 15733-15740. [3] Eidenmüller, J., et al. (2000) Biochemistry 39, 13166-13175. [4] Shahani, N., and Brandt, R. (2002) Cell. Mol. Life Sci. 59, 1668-1680. [5] Fath, T., et al. (2002) J. Neurosci. 22, 9733-9741.

Structure of the group Group leader Roland Brandt Postdoctoral fellows Neelam Shahani Graduate students Thomas Fath, Julia Leschik, Nina Lüdemann, Jörg Piontek Zsofia Sebö Technician Claudia Mandl

Contact Prof. Dr. Roland Brandt Abteilung Neurobiologie Fachbereich Biologie/Chemie Universität Osnabrück Barbarastraße 11 49076 Osnabrück Germany A +49-(0) 541 - 969 2338 E +49-(0) 541 - 969 2354 K [email protected] http://www.biologie.uni-osnabrueck.de/

29 Research Profiles Neural stem cell development and role vide fundamental insight into of calcium signalling in neural precursor brain functioning. differentiation Neural stem cell development Francesca Ciccolini Embryonic and adult neural stem cells are both defined PhD 1994 University of Rome "La Sapienza", Italy by their ability to generate Postdoctoral work at Cambridge University, UK more stem cells (self- Group Leader at the Department of Neurobiology, IZN, since 2002 renewal) and to give rise to multiple cell types (multipo- Current Research tentiality). Despite these common features, neural Neural stem cells capable of generating neurons and macro- stem cells during development modify their properties glia are present both in the embryonic and adult mammalian according to temporal and regional clues. For example, neu- brain. Since neural stem cells can be grown and differenti- ral stem cells from different brain regions give rise to region- ated in vitro they have attracted great interest mainly as a specific progeny. Similarly, early and late stem cells differ in potential source of trasplantable tissue. However, neural their ability to respond to growth factors, cell phenotype, stem cells play also a major physiological role in the context and differentiation potential. The reasons regulating these of the embryonic as well as adult brain. In recent years, the modifications are not understood. Fundamental questions notion that the generation of neurons in the mammalian are which are the molecular mechanisms underlying these central nervous system stops shortly after birth has been changes? Which signals are regulating these modifications? challenged. Indeed, in certain regions of the brain, neuro- Do these modifications reflect a change in the physiological genesis persists throughout the adult life and the newly gen- role of neural stem cells? One of the major problems in erated neurons may be important for memory formation and answering these questions is the absence of neural stem repair of small cellular losses. Thus, understanding how neu- cells markers to allow direct neural stem cell studies. Our ral stem cell proliferation and differentiation is regulated may focus is to find strategies to isolate and purify neural stem lead not only to a major clinical breakthrough but also pro- cells from different developmental stages to directly study them.

Calcium signalling during neural stem cell differentiation The proliferation and differentiation of neural stem cells are regulated by environmental signals and by cell-cell interactions. How this variety of signals interacts to direct neural precursor behaviour is not understood. While many growth and neurotrophic factors can influence neuronal differentiation, several lines of evidence suggest that Ca2+ signals may Fig. 1 Early and late development stem cells differ in their ability to be key regulators of this process. Changes in the intracellular respond to growth factors. Ca2+ concentration as a result of spontaneous or signal-reg- Early development neural stem cells respond to FGF-2 (F) while later ulated events are a characteristic of many developmental they increase levels of EGFR expression and become responsive to systems and appear to be involved in the initiation of the both EGF and FGF-2 (E/F). This change in EGF responsiveness can be recapitulated in vitro by treating early stem cells with FGF-2. differentiation process. We recently found that progenitors

30 Francesca Ciccolini derived from neural stem cells generate spontaneous calcium ulated at the level of EGFR expression and can be induced in signals during the process of differentiation. Key questions early stem cells by a brief exposure to FGF-2. Thus EGFR, are: What is the functional significance of these calcium alone or in combination with other differentiation stage spe- events? What is the relationship between calcium signals cific markers, can be a very powerful tool to purify small cel- and known modulators of neural precursor differentiation? lular subset highly enriched in stem cells from the embryonic We are using cultures enriched in neural stem cells to study brain. the effect of calcium signalling on neural stem cell differentiation. Spontaneous calcium signals We want to understand the role of the spontaneous calcium signals in neural stem cell proliferation and differentiation. In particular we are interested to investigate whether these calcium signals regulate the timing of neural precursor division. To this end we will set up conditions to modulate the frequency of these events and to determine the effect of these modulations on neural precursor cell cycle and the onset of differentiation.

Selected Publications

[1] Ciccolini F, Svendsen CN (1998) J. Neurosci., 18: 7869-7880. [2] Giarre M, Caldeira S, Malanchi I, Ciccolini F, Leao MJ, Tommasino M (2001) J.l Virology, 75: 4705-12. [3] Ciccolini F (2001) Mol. Cell Neurosci., 17: 895-907. [4] Ciccolini F, Svendsen CN (2001) J. Mol. Neurosci., 17: 25-33. [5] Ciccolini F, Collins TJ, Sudhoelter J, Lipp P, Berridge MJ, Bootman M D (2003) J. Neurosci, 23.

Structure of the group Fig. 2 Spontaneous local and global Ca2+ signals in neurosphere-derived precursors. (a, b) Confocal images and corresponding traces Group leader Francesca Ciccolini showing examples of spontaneous global (a) and local (b) changes in Graduate student Nidhi Gakhar the intracellular Ca2+ concentration. Arrows point at the subcellular Technician Claudia Mandl region from which Ca2+ changes were analysed. Arrowheads beneath the traces indicate the particular Ca2+ signals shown in the corresponding image. Contact Dr. Francesca Ciccolini Future Projects and Goals IZN, Neurobiologie Growth factor responsiveness to find neural stem cells Universität Heidelberg Im Neuenheimer Feld 345 The major focus of the lab is to use FACS-based techniques 69120 Heidelberg to isolate neural stem cells from embryonic and adult mam- Germany malian brain to allow direct neural stem cell studies. We A +49-(0) 6221 - 54 8696 recently found that a hallmark of the transition between E early and late neural stem cells is the acquisition of EGF +49-(0) 6221 - 54 6700 K responsiveness. This ability to respond to EGF is mostly reg- [email protected]

31 Research Profiles Development of nerve cells and line biosynthesis as a synex- pression group that is generation of neuronal diversity conserved in evolution from birds to mammals. Uwe Ernsberger Common mechanisms for 1985-1988 PhD: Max-Planck-Institute for Psychiatry, Martinsried, and inducing transmitter syn- Christian-Albrechts-University, Kiel, thesis and release genes 1988-1991 University of California, San Diego, USA: Research Fellow of the DFG and MDA Synaptotagmin I as a putative 1992-1998 Max-Planck-Institute for Brain Research, Frankfurt, calcium sensor of transmitter since 1999 IZN and Department of Anatomy, Ruprecht-Karls- release and neurexin I as a University, Heidelberg putative organizer of synaptic protein complexes are Current Research general neuronal genes expressed in many classes of neurons. They become detectable in sympathetic neurons In recent years, significant progress has been made to shortly after acquisition of the noradrenergic phenotype. understand the generation of neuronal diversity. The peri- Overexpression studies show that both genes can be pheral sympathetic ganglia of mammals and birds constitute induced by BMP growth factors and Phox2 transcription fac- one of the key models used for the study of this question. tors. Thus, it appears that induction of general and popula- They contain two neuron populations which develop from tion-specific neuronal characters involves common the same precursor pool but differ in their transmitter, nor- mechanisms. adrenaline and acetylcholine, respectively. In addition, endocrine cells of the adrenal medulla are also derived from these Neuronal maturation precursors. Our interest is to unravel growth factors and and bifurcation of neuronal and endocrine lineages transcription factors which are crucially involved in the regu- Induction of noradrenergic and general neuronal properties lation of these differentiation paths. Analysis of signals regu- does not lead directly to a mature sympathetic neuron. Fur- lating general neuronal genes such as neurofilaments or ther differentiation is accompagnied by increased expression neurexins will shed light on the bifurcation of neuronal and of synaptotagmin I and neurexin I. In contrast, adrenal chro- endocrine lineages. Characterizing signals regulating neuron maffin cells show reduced or no expression of these and population-specific traits such as transmitter-synthesizing other general neuronal markers such as neurofilament M and enzymes will show how diversification of neuronal lineages SCG10. Thus, the maturation of neuronal gene expression is operates. an essential landmark of neuron differentiation and of bifur-

Noradrenergic induction – General neuronal markers such as SCG10 and NF- specifying neurons by coordinate gene expression M (neurofilament M) are expressed in a large Noradrenergic properties are induced early during sympa- number if not all neuron classes. thetic neurogenesis by BMP growth factors and Phox2 transcription factors in birds and mammals. Comparing the expression of tyrosine hydroxylase and dopamine β-hydroxylase, we could show that these two enzymes in the norad- Population-specific neuronal markers are ex- renaline biosynthesis cascade are expressed at the same pressed in restricted neuron classes such as TH (tyrosine hydroxylase) in the sympathetic ganglia time. The induction by the same growth and transcription on this trunk cross section. factors suggests regulation of these enzymes of noradrena- 32 Uwe Ernsberger

In addition, we analyze the diversification of transmitter properties in sympathetic ganglia. c-ret function in chick and mouse embryos is altered to demonstrate the role of c-ret signaling in cholinergic differentiation and bifurcation of neuronal differentiation paths.

With this approach we want to show how differentiation and diversification are regulated to orchestrate the expression of general neuronal properties with the acquisition of popula- Schematic representation of a transmitter vesicle, the transmitter syn- tion-specific characters during neuronal development. thesizing enzymes tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH), and certain proteins involved in vesicle fusion and transmitter release. SNAP-25 (S25), synaptotagmins (SYT), neurexins Selected Publications (NEU), and voltage-gated calcium channels (Ca-K) are involved in dif- [1] Patzke, H., Ernsberger, U. (2000) Mol Cell Neurosci 15, 561-572. ferent functional aspects of transmitter release and are addressed in our [2] Ernsberger, U. (2000) Eur J Biochem 267, 6976-6981. studies. [3] Patzke, H., et al. (2001). Mech Dev 108, 149-159. [4] Ernsberger, U. (2001). Auton Neurosci 94, 1-13. cation of neuronal and endocrine lineages. [5] Burau, K., et al. (2002). Soc Neurosci Abstr, 231.11.

Generation of neuronal diversity in sympathetic ganglia Structure of the Group Choline acetyltransferase (ChAT) and the vesicular acetyl- Group leader Uwe Ernsberger choline transporter (VAChT) are two main features of cholin- Graduate students Karin Burau ergic neurons which are coordinately transcribed from the Lorena Esposito cholinergic gene locus. The loss of ChAT and VAChT expres- Technicians Sandra Partimo sion in sympathetic ganglia of c-ret mutant mice indicates Ingrid Stenull that signaling via receptors for growth factors of the GDNF family is necessary for the development of cholinergic sym- Contact pathetic neurons. Expression of c-ret in cholinergic sympathetic neurons of the chick embryo suggests that its role PD Dr. Uwe Ernsberger may be evolutionary conserved. Thus, signaling via BMP and IZN, Institut für Anatomie und Zellbiologie, Abt. Neuroanatomie GDNF family receptors contributes to the generation of neu- Im Neuenheimer Feld 307 ronal diversity in the sympathetic system. 69120 Heidelberg Germany A Future Research and Goals +49-(0) 6221 - 54 8344 E +49-(0) 6221 - 54 5604 BMP growth factors and Phox2 transcription factors may not K [email protected] suffice to generate mature sympathetic neurons. Rather a partially differentiated cell type seems to result which may correspond to the sympathoadrenal progenitor. Studying the expression of general neuronal genes, we are searching for factors which may be essential for the maturation of neuronal properties and the bifurcation of neuronal and endocrine lineages.

33 Research Profiles Membrane traffic in neuronal cell ing in combination with in vitro motility assays and bio- systems chemical approaches, the recruitment and regulation of Hans-Hermann Gerdes the respective motor proteins is under investigation. One PhD 1984 University of Marburg,Germany emphasis is to analyze Postdoctoral work at Marburg University and EMBL, Heidelberg, whether myosins play a role in Germany in the maturation of SGs. Fur- Group Leader at the Department of Neurobiology, IZN, since 1991 thermore we are interested in analyzing the mechanism of Current Research axon-specific targeting of SGs in polarized neurons. Signal transmission between neurons occurs mostly at chemical synapses, which represent functionally and structurally Dendritic membrane traffic highly specialized contact points between axons and dendrites. At presynaptic axonal endings signaling molecules are The dendritic tree comprises one of the most complex sub- liberated from two types of neurosecretory vesicles: the domain structures of the plasma membrane and very little is small synaptic vesicles (SSVs) containing classical neu- known about trafficking pathways involved in the formation rotransmitters such as GABA and neurosecretory granules and maintainance of this structure. We are focussing on the (SGs) storing neuropeptides. Neuropeptides play a major transport of neurotransmitter receptors as one of the most role in modulation of neurotransmission. At the postsyn- prominent protein classes in dendrites. These receptors are apses of dendrites, signaling molecules of other neurons are composed of several subunits and vary in subunit composi- perceived by neurotransmitter and hormone receptors. Our ton throughout the dendritic tree. One possibility is that research focusses on two aspects of membrane traffic under- their differences in structure result in differences in synaptic lying synaptic transmission: axonal transport of SGs and plasticity. To analyze how membrane traffic is linked to syn- dendritic transport of neurotransmitter receptors. aptic plasticity, we are studying the selective transport of GFP-tagged subunits of the GABAA receptor to postsynapes Biogenesis and transport of secretory granules by multi-color imaging in combination with biochemical Secretory granules (SGs) are formed as short-lived vesicular approaches. One interesting observation is that the differ- intermediates at the trans-Golgi network. These intermedi- ential trafficking of selected subunits depends on the devel- ates undergo a complex and poorly understood maturation opmental stage of hippocampal neurons. We are currently process resulting in mature SGs. A major objective of our addressing the correlative transport dynamics, the site of laboratory has been to study the sorting of neuropeptides integration into the plasma membrane and the endocytosis into SGs. This led to the identification of a specific sorting rate of the respective receptor subunits during neuronal signal. To gain insight into the transport dynamics of newly development. formed SGs, we express GFP fusion proteins to specifically label SGs in living cells. This facilitates the study of budding, Future Projects and Goals transport and docking of SGs in real time. One of our sur- One major goal is the characterization of the structural sort- prising findings is that SGs from neuroendocrine PC12 ing determinants of neurotransmitter receptor subunits and cells possess a dual transport system: after microtuble- the identification of proteins interacting with these domains. dependent delivery to the cell periphery, SGs exhibit a myo- Furthermore, we will study dendritic traffic in a more physio- sin-dependent transport leading to their restriction and logical context using organotypic cultures of brain tissue. By even dispersal in the F-actin rich cortex. Using live cell imag- 34 Hans-Hermann Gerdes combining optical methods with computer-based Selected Publications approaches, we will pursue a time-resolved, 3-dimensional [1] Glombik, M., Krömer, A., Salm, T., Huttner, W.B., Gerdes, H.-H. (1999). reconstruction of dendritic transport in neuronal networks. EMBO J. 18: 1059-1070. [2] Rudolph, R., Salm, T., Rustom, A., Gerdes, H.- H. (2001). Mol. Biol. Cell:12, 1353-1365. [3] Rustom, A., Bajohrs, M., Kaether, C., Keller, P., Toomre, D., Corbeil, D., Gerdes, H.-H. (2002). Traffic 3: 279-88. [4] Rudolph, R., Salm, T., Kuznetsov, S. A., Schlicker, O., Hellwig, A., Hammer, J. A., Gerdes, H.- H. J. Cell Sci., in press.

Structure of the group Group leader Hans-Hermann Gerdes Graduate students Mark Bajohrs Ta n j a Kö g e l Amin Rustom Oliver Schlicker Undergraduate student Nickolay V. Bukoreshtliev Technician Sigried Riese Senior scientist Sergei Kuznetsov

Figure1. Scheme illustrating the role of myosin Va in the transport of Contact secretory granules. After microtubule-dependent delivery to the cell periphery, myosin Va facilitates the distribution of SGs in the F-actin PD Dr. Hans-Hermann Gerdes rich cortex. TGN, trans-Golgi network; MT, microtubule; PM, plasmam- IZN, Neurobiologie Im Neuenheimer Feld 364 69120 Heidelberg Germany A +49-(0)6221 - 54 8317 E +49-(0)6221 - 54 8301 K [email protected] www.nbio.uni-heidelberg.de/Gerdes

Figure 2. Expression of GABA-A receptor subunit α1 fused to EYFP in primary hippocampal neurons cultured for 4 days (A) or 10 days (B). Note the diffuse flourescence pattern of α1-EYFP up to 4DIV (A) and the clustered fluorescence signals at 10DIV (B, arrow heads)

35 Research Profiles 1. Peripheral and spinal mechanisms of Experiments employing a block of primary afferent muscle pain fibres from muscle and skin 2. Neurotransmitters involved in the with tetrodotoxin (TTX) neuromodulation of the reflex bladder demonstrated that many of the nociceptive fibres from muscle possess TTX-resis- Siegfried Mense tant sodium channels, and that the group IV-fibre input Dr. med., Universität Bonn 1973; Assistant Professor, University of from muscle is subject to a North Carolina at Chapel Hill, USA, 1978-1979; Habilitation, stronger inhibition by large Universität Kiel, 1979; Universitätsprofessor, Universität Heidelberg afferent fibres than is the 1985 cutaneous C-fibre input.

Current Research Spinal level 1. Muscle pain. Peripheral level Previous studies of our group had demonstrated that the In experimental animals in vivo, the hypothesis is being gaseous transmitter nitric oxide (NO) has a direct inhibitory tested if purinergic and vanilloid receptors - which were orig- action on nociceptive dorsal horn neurones, or conversely, inally detected on nociceptive endings in the skin - are also that a spinal lack of NO is an excitatory stimulus for these present on muscle nociceptors. Single fibre recordings from cells. From evidence in the literature it appears, however, that nociceptive muscle afferents have shown that ATP, capsaicin, at the supraspinal level NO has a pronociceptive or pro- and acidic solutions (pH 5 and 6) are effective stimulants hyperalgesic action. for muscle nociceptors. This finding is also of clinical importance, because muscle inflammation and ischemia, respec- In follow-up experiments we investigated the role of cyclic tively, are associated with a lowered pH. Therefore, the pain guanosine monophosphate (cGMP) in these NO actions. of myositis and intermittent claudication are likely to be The results obtained so far support the assumption that the mediated by nocicepive endings equipped with vanilloid effects of NO are mediated through the NO-cGMP pathway: receptors. In contrast, the pain of muscle trauma – which is a lack of cGMP induced in the spinal cord by spinal superfu- associated with necrosis of muscle fibers and release of ATP sion with a blocker of the NO-sensitive guanylyl cyclase - could be mediated by endings expressing purinergic recep- (ODQ) was followed by an activation of nociceptive neu- tors. rones as was lack of NO. A spinal increase of cGMP caused by superfusion with a phosphodiesterase V blocker (sildena- In the literature, the hypothesis has been formulated that fil) had no effect on the discharges of the dorsal horn neu- nociceptive endings (in the skin) possess either purinergic rones. In contrast, sildenafil administered supraspinally by or vanilloid receptors. This hypothesis appears not to be injection into the third cerebral ventricle (Fig. 1) had an exci- true for muscle nociceptors, because many endings recorded tatory action on the spinal sensory neurones. These data by our group responded to both ATP and acidic solutions. show that the NO-cGMP pathway has an opposite action on To exclude an influence of the acidic nature of the ATP solu- sensory neurones at the spinal and supraspinal level. Follow- tion, the solution was adjusted to a pH of 7.4. Immunohis- ing systemic (oral) administration of sildenafil, the excitatory tochemical evalutions of DRG cells stained retrogradely from supraspinal actions appear to prevail, because the effect the sural muscle likewise showed that a considerable propor- consisted in an activation of sensory spinal neurones. tion of neurones expressed both P2X3 and VR-1 receptors.

36 Siegfried Mense

2. Neuromodulation of hyperactive urinary bladder A further goal is to investigate the role of glial cells in the Neuromodulation was performed by electrical stimulation of mediation of muscle pain. sacral nerves through electrodes positioned in the sacral foramen S1 (sacral neuromodulation) in rats with an inflam- Reflex bladder. The next question to solve is the identity of matory reflex bladder. The first experimental data indicate the neurotransmitters/neuromodulators that are released by that activation of thick afferent fibres (at low intensities of sacral neuromodulation from the primary afferent fibres and stimulation) has weaker effects on the hyperactivity of the that influence the hyperactivity of the reflex bladder. bladder than activation of thin fibres (at high intensities of stimulation). Short periods of stimulation caused inhibitions Selected publications from 1999 to 2002 or reductions of the hyperactivity of the bladder that out- [1] Callsen-Cencic, P. and Mense, S. (1999) BJU International 84, 1084- lasted the period of stimulation by far. In conclusion, short 1092 periods of sacral stimulation at high intensities appear to be [2] Hoheisel, U., et al. (2000) Pain 88, 249-257 the most effective method to reduce the hyperactivity of an [3] Steffens, H., et al., (2001) Neuroscience Res. 39, 413-419 inflammatory reflex bladder. [4] Graven-Nielsen, T., et al., (2002) J. Physiol. 540.2, 647-656 [5] Mense, S. (2002) J. Pain 3, 264-267 Future projects and goals Structure of the group Muscle pain. Future experiments will address the potential role of growth hormones, neurotrophic factors, and cytok- Group leader Siegfried Mense ines (BDNF, NGF, TNF-α, GDNF) as well as of NO as activat- Postdoctoral fellows Ulrich Hoheisel, Seyed-Hossein Riazimand ing or sensitising agents of peripheral muscle nociceptors. Heinz Steffens, Peter Trudrung Since some of these agents are likely to have different Doctoral students Aurelia Fleck, Jochen Reinöhl, actions in intact and pathologically altered tissues, the Caroline Scheifer experiments will be performed in rats with intact and Technicians Marina Szymbara, Beate Quenzer inflamed muscle. Contact Prof. Dr. med. Siegfried Mense IZN, Institut für Anatomie und Zellbiologie, Abt. Neuroanatomie Universität Heidelberg Im Neuenheimer Feld 307 D-69120 Heidelberg Germany A +49-(0)6221-54 4193 E +49-(0)6221-54 6071 K [email protected]

Fig. 1 Impulse activity of lumbar dorsal horn neurones following intacerebroventricular (i.c.v.) injection of sildenafil to increase the cGMP concentration at the supraspinal level. A) Original registrations of spontaneous impulse activity. B) Impulse activity of 3 single dorsal horn neurones following i.c.v. injections (arrows) of artificial cerebrospinal fluid (CSF; control) and sildenafil in CSF. C) Activity of 15 dorsal horn neurones following supraspinal administration of sildenafil and CSF, respectively. 37 Research Profiles Neuronal synchrony and plasticity nocytochemistry in brain slices and the generation of Hannah Monyer transgenic mice with altered expression of critical genes M.D. 1983, University of Heidelberg (e.g. AMPA receptors, Postdoctoral work at Stanford University Medical Center, Department metabotropic glutamate of Neurology receptors, connexins) in Group leader at the ZMBH GABAergic interneurones. Medical Director of the Department of Clinical Neurobiology, University Hospital of Neurology, IZN, since 1999 Given the large diversity of GABAergic interneurones Current Research (based on the presence of certain parameters, for The studies of this lab are directed at the identification of instance chemical markers, morphological criteria, connec- genes critically involved in the generation of synchronous tivities), present projects aim at the identification of oscillation in neuronal networks and on the role of NMDA GABAergic subpopulations of neurones (e.g. parvalbumin-, receptor subtypes in different forms of plasticity. somatostatin-, calretinin-positive cells). To this end transgenic mice are produced in which these neuronal subpopula- Molecular mechanisms underlying synchronous activity in tions are labelled using the in vivo marker green fluorescent the central nervous system protein. The subsequent electrophysiological studies on flu- Molecular and functional characterization of native orescent neurones in these mice should aid in identifying glutamate receptors in identified neurones has revealed that the GABAergic cell types involved in different forms of net- GABAergic interneurones are endowed with receptors that work oscillations. are functionally different from those present in glutamatergic principal cells. The differential expression of glutamate Finally, these studies include the identification of neurones receptors in these subsets of neurones is not restricted to that are electrically coupled via gap junctions and the eluci- glutamate receptors but has been extended to other gene dation of their role in the generation of oscillatory and syn- families. The repertoire of receptors expressed in GABAergic chronous activity. interneurones is of particular interest in view of the growing evidence that their functional role extends beyond providing NMDA receptors neuronal plasticity and vulnerability the main source of inhibition in the adult CNS. A number of The NMDA receptor, a subtype of the glutamate receptor compelling studies and computational simulations data pro- family, is critical for the induction of different forms of plas- vide evidence that networks of inhibitory neurones play a tic changes in the brain. Molecular and functional character- pivotal role in the generation of certain forms of oscillations ization of different NMDA receptor subtypes has revealed that arise as a network property. Oscillatory activity in the critical amino acids that confer the receptor different prop- gamma frequency range (40 Hz) has been proposed to be erties with respect to kinetics, channel block by magnesium, critical for object representation using temporal coding. sensitivity to pH etc. The differential regulation of NMDA receptor subtype expression with respect to brain areas and The goal of our studies is to identify the 'key' molecules in cell types exerts an important function in the developmen- GABAergic interneurones that underlie oscillatory activity tally regulated change of neuronal plasticity. and that are involved in controlling synchronous firing of ensembles. The individual projects entail single-cell PCR in Projects pertaining to this research programme aim at defin- the acute slice preparation, in situ hybridization and immu- ing the molecular basis of the differential NMDA receptor

38 Hannah Monyer efficacy and include the generation of transgenic mice in Selected Publications which the switch from the 'young' to the 'adult' form of [1] Venance, L., et al. (2000) Proc. Natl. Acad. Sci. USA 97, 10260-10265 NMDA receptors is prevented and studies of the cellular [2] Fuchs, E. C., et al. (2001) Proc. Natl. Acad. Sci. USA 98, 3571-3576 localization of the 'young' form of NMDA receptors. The [3] Hormuzdi, S.G., et al. (2001) Neuron 31, 487-495 analysis of these mice is performed using electrophysiologi- [4] Meyer, A.H., et al. (2002) J. Neurosci. 22, 7055-7064 cal techniques. Structure of the group In cell culture obtained from cortical neurones, excitotoxic vulnerability is tested and the possible differential involve- Group leader Hannah Monyer ment of specific receptor suptypes is investigated. Postdoctoral fellows Antonio Caputi, Jakob von Engelhardt Elke Fuchs, Anca Grigorescu-Sido, Anne Future Projects and Goals Herb, Sheriar Hormuzdi Graduate students Maria Blatow, Irina Coserea So far our studies regarding GABAergic network activity and Mikhail Filippov, Dragos Inta related projects entailed molecular, functional (electrophysi- Undergrad. students Michael Barbe, Christine Bark ological) and anatomical characterization of receptor expres- Ingo Helbig, Patricia Timmermann sion in identified cell population. The link to behaviour has Thorsten Schächinger, Lars Tönges been missing so far. It is our aim to add this aspect to our Technicians Ulrike Amtmann, Regina Hinz-Herkommer work. Also, one project pertaining to the identification of downstream cascades after NMDA receptor overstimulation Contact will entail chip analysis. Prof. Dr. Hannah Monyer IZN, Abt. Klinische Neurobiologie der Neurologischen Universitätsklinik Im Neuenheimer Feld 364 D-69120 Heidelberg Germany A +49-(0)6221 -56 2401, E +49-(0)6221-56 1397 K [email protected] http://www.KlinNbio.uni-hd.de

Fig. 1 Subpopulations of electrically coupled GABAergic interneu- Fig. 2 In situ hybridization showing developmental regulation of the rones form distinct networks promoting synchronous NR2A but not NR2B subunit (left panels). Cortical cultures (A) are neuronal activity. vulnerable to glutamate receptor induced toxicity (B, in blue staining indicate dead cells after ten minutes of NMDA exposure).

39 Research Profiles Mechanisms of short lasting synaptic not only low release rate, but plasticity also relatively long diffusional distance between Ca2+ chan- 2+ Andrei Rozov nels and Ca sensor. Addi- tionally, in the same study we PhD 2000, University of Heidelberg have proposed a novel mech- Postdoctoral work at Free University of Amsterdam, Department of anism for paired pulse facili- Neurophysiology tation, which can operate in Group leader in the Department of Clinical Neurology, University terminals with an increased Hospital of Neurology buffer capacity and can arise IZN, since 2002 from the local partial saturation of Ca2+ buffers. Current Research Recently we have found evidence that this mechanism indeed underlies facilitation in calbindin-D28K containing Short-term modifications in the efficacy of synapses are terminals (Figure 2). observed in synaptic connections of the central nervous system when the presynaptic neuron is repetitively active. Suc- In addition we are involved in studies of 1) the contribution cessive unitary postsynaptic potentials, evoked by a train of of AMPAR desensitization to synaptic depression 2) mecha- presynaptic action potentials, can increase (facilitate) or nisms of LTP induction 3) electrical coupling between corti- decrease (depress) in amplitude, depending on the identity cal interneurons. of the two neurons that form a connection. An increase of the probability of transmitter release caused by successive Future Projects and Goals APs in the presynaptic terminal is postulated to underlie short-term facilitation of PSPs. Short-term synaptic In the future we would like to pursue investigation of general enhancement occurring in the time scale of tens of millisec- mechanisms of synaptic plasticity mainly in two directions 1) onds to several seconds is thought to be a calcium depen- How do postsynaptic density proteins participate in long dent process. The intracellular concentration of calcium at lasting changes of synaptic strength. 2) How do mGluR and the release site depends on the distance between Ca2+ GABAB-receptors contribute to synaptic depression. How- ever, the most interesting topic is: what is the functional channels and the Ca2+ sensor as well as on the properties of 2+ meaning of short-lasting synaptic changes at the system endogenous Ca buffers. It has been generally accepted level. Addressing this question one requires the combination that short-lasting synaptic enhancement is entirely presyn- of molecular biological assays, in particular transgenic aptic and involves an additional Ca2+ sensor, which is differ- approaches, with modern physiological techniques. For ent from the one responsible for the transmitter release. instance, voltage sensitive dye imaging from a single neuron and large brain regions may provide information about the However, we have shown first, that at synapses characterized role of facilitation and depression in lateral and recurrent by high release probability and expressing Ca2+ permeable, inhibition; two photon microscopy can be used to measure polyamine sensitive AMPA receptor channels on the from very small structures like spines and presynaptic termi- postsynaptic site, rapid activity dependent relief from nals; whole cell in vivo recording allows not only recording polyamine block increases postsynaptic responses (Figure from cells under physiological conditions but also the use of 1). Second, we have demonstrated that at neocortical exci- physiological stimulation instead of artificial current injec- tatory connections facilitation is due to accumulation of free tion. Ca2+. We suggest that at these synapses facilitation requires 40 Andrei Rozov

Contact Andrei Rozov IZN, Department of Clinical Neurobiology, University Hospital for Neurology, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany A +49-(0)6221-56 2415 / 2420 E +49-(0)6221-56 1397 K [email protected]

Figure 1. Simultaneous whole-cell recordings were made at 34°C and 1.6 mM extracellular Ca2+ from a triplet (schematically shown on top) in which the same pyramidal neuron (P) innervated two multipolar interneurons (M). One multipolar cell (M1) was loaded with the PA-containing, another (M2) with the PA-free intracellular solutions. EPSPs evoked by 2 action potentials elicited in the pyramidal cell at 20 Hz fa- cilitated in M1 (left trace) and depressed in M2 (right trace). The plot shows pairwise comparison of EPSP2/EPSP1 ratios measured from tri- plets. The connected symbols represent amplitude ratios of EPSPs evoked simultaneously in multipolar interneurons loaded with the PA- containing (closed circles) and with the PA-free (open circles) intracellular solutions following 20 Hz stimulation of the same presynaptic pyramidal neuron.

Selected Publications

[1] Rozov A., et al (1998) J Physiol. 511, 361-377. [2] Rozov A. & Burnashev N. (1999) Nature 401, 594-598. Figure 2. EPSCs recorded from CA3 pyramidal cells during paired- [3] Rozov A., et al (2001). J Physiol. 531, 807-826. pulse stimulation (10 Hz) of mossy fibers in WT (MF, upper traces) [4] Rozov A., et al (2001) J Neurosci. 21, 8062-8071. and CB-KO mice (MF CB-KO, lower traces) In MF an increase of 2+ 2+ [5] Meyer AH, et al (2002) J Neurosci. 22, 7055-7064 [Ca ]o increases facilitation, a decrease of [Ca ]o reduces facilita- 2+ tion. In MF CB-KO an increase of [Ca ]o reduces facilitation, a de- 2+ crease of [Ca ]o increases facilitation. B, The graph compares the Structure of the group 2+ effects of changes in [Ca ]o on facilitation at MF to CA3 pyramidal Group leader Andrei Rozov cell synapses (open squares) with that at MF to CA3 pyramidal cell synapses in CB-KO mice (closed circles). In order to compare across Postdoctoral fellow Elke Fuchs several experiments made on different connections, PPRs were nor- Graduate student Maria Blatow 2+ malized to that measured in 2 mM [Ca ]o Technician Marlies Kaiser

41 Research Profiles Development and maintenance of and successfully linked to cellular properties of this midbrain dopaminergic neurons neuronal population. We recently showed that two Horst Simon closely related transcription factors, engrailed-1 and Diplom in Biochemistry and Molecular Biology, ETH-Zürich, Switzerland engrailed-2, are cell autono- Ph.D. with Andrew Lumsden, Guy's Hospital, University of London, UK mously required for the sur- Postdoc with Dennis O'Leary, The Salk Institute, La Jolla, CA, USA vival of dopaminergic Group Leader, Anatomy and Cell Biology III since 1999 neurons in the SNC. Lack of all four alleles of the two Current Research transcription factors in mutant mice or their silenc- The research of our laboratory is directed to the molecules ing by RNA interference in primary cell culture induces involved in the development and adult maintenance of the caspase-3 dependent apoptotic cell death in postmitotic midbrain dopaminergic (mDA) neurons. We investigate the dopaminergic neurons. This is similar to the mechanism that genes involved in their induction, determination of their cell has been suggested to be responsible for the degeneration fate, establishment and maintenance of their axonal projec- of this cell group in Parkinson's patients or in the case of tions and their synaptic connections as well as those that neurotoxin-induced depletion of nigral dopaminergic neu- are essential for their survival. Our approaches are gain of rons in animal models of PD. Mutant mice lacking three alle- function experiments introducing over-expression vectors in les (En1-/+;En2-/-) exhibit a specific, progressive loss of cell culture and in chicken embryos by electroporation, and dopaminergic neurons in the lateral SNC, the population of loss of function studies involving homologous recombinant knockout mutant mice, conditional mutant mice based on the loxP/Cre system and RNA interference on primary cell culture.

Transcriptional Regulation of their Cell Fate Midbrain dopaminergic neurons are the largest source of dopamine in the mammalian central nervous system, located in three distinct nuclei, substantia nigra compacta (SNC), the ventral tegmentum and the retrorubral field. They are associated to one of the most prominent human neurological disorders, Parkinson’s Disease (PD). PD is caused by the Fig. 1: Dopamine circuit in the rat brain degenerative loss of the dopaminergic neurons in the SNC, which leads to a diminished release of dopamine in the basal cells most affected in human patients. Interestingly, α-Synu- ganglia, one of the major centers of voluntary motor control. clein, a gene that has been recently genetically linked to the The symptoms are tremor, muscular rigidity, akinesia and loss of midbrain dopaminergic neurons during Parkinson's loss of postural reflex. The disease affects approximately 2% Disease, seems to be regulated by engrailed-1 and -2. of the human population when they are over 65 years of age. Our recently performed differential display experiment revealed amongst others two more transcription factors spe- Despite the medical relevance of midbrain dopaminergic cifically expressed by midbrain dopaminergic neurons, these neurons, only a few regulatory elements have been identified 42 Horst Simon are the homeobox transcription factor, Pbx1, and the winged Selected Publications helix transcription factor, HNFα. Analysis of the Pbx1 null [1] Yee, K.T. ; Simon, H.H; Litwack, D.; Tessier-Lavigne, M.; O’Leary, D.D.M. mutants revealed an involvement in axonal pathway finding Neuron (1999) 24 (3), 607-622 related to the release of a chemoattractive diffusible factor [2] Simon, H.H.; Saueressig, H.; Wurst, W.; Goulding, M.D.; O’Leary, D.D.M from the developing basal ganglia, the main innervation tar- Journal of Neuroscience (2001) 21 (9) 3126-34 get of this neuronal population. HNF3α is likely involved in [3] Simon H.H., Bhatt, L., Gherbassi, D., Sgadó P. and Alberí, L.; N.Y. Acad. the regulation of KATP channels. In midbrain dopaminergic Sci (2003), in press. [4] S.Thuret, M.Gassmann, K. Lloyd., R. Klein, R.H. Dyck and H.H. Simon neurons, the most prominent KATP channel is a complex of two proteins, Sur1 and Kir6.2. Loss of function studies on Submitted [5] L. Alberi, C. Scholz, S. Thuret C. Logan and H.H. Simon. Submitted mutant mice revealed that they are survival relevant for the midbrain dopaminergic neurons. Mice deficient of either of Structure of the group the two genes show a progressive loss of dopaminergic cells in the SNC after birth. Group leader Horst Simon Graduate students Lavinia Alberi Future Projects and Goals Lavinia Bhatt Daniel Gherbassi Our long term goal is the identification and charaterization Christian Scholz of the transcriptional networks which determines the cellular Paola Sgado properties of the mDA neurons. This includes the transcrip- Technician Gabi Döderlein tion factors as well as downstream molecules. One emphasis is the identification of genes which cause or avoid physio- Contact logical stress in this neuronal population potentially linking them PD. A long term aim is the establishment of cell culture Dr. Horst Simon systems which mimic this physiological stress and may be IZN, Department of Anatomy and Cell Biology, Neuroanatomy usuable to screen for active pharmacological components. Im Neuenheimer Feld 307 69120 Heidelberg Germany A +49-(0) 6221 - 54 8342 E +49-(0) 6221 - 54 5605 K [email protected]

Figure 2: Specific loss of dopaminegic neurons in lateral substantia nigra compacta (SNC) of adult mutant mice, heterozygous for the En1 null mutation and homozygous for the En2 null mutation (En-1+/-;En2-/-)

Figure 3: Caspase dependent apoptotic cell death in engrailed deficient mDA neurons

43 Research Profiles Molecular cell biology of neuron-glia antibodies against NG2: this may contribute to the poor interaction and myelination repair seen in these patients as the precursor cells respon- Jacqueline Trotter sible for remyelination are attacked. Additionally, the PhD 1979 University of York, England, antibodies may be interfering Postdoctoral work at the Max-Planck Institut für Immunbiologie, with synaptic function. We Germany, Stanford University School of Medicine, USA and the have cloned mouse NG2 and University of Heidelberg generated fusion proteins Group Leader at the Department of Neurobiology, IZN, since 1991. July and specific antisera for the 1999 Hermann and Lilly Schilling Stiftung Professor for Neuroscience, different regions of the mole- Dept. of Neurobiolgy, University of Heidelberg. April 2000: cule. These provide tools to C3Professor of Cell Biology at the University of Mainz. investigate the function of the molecule. We have recently shown that the C-terminus of NG2 binds to the PDZ protein Current Research GRIP and thus forms a complex with AMPA receptors in synaptic glia and immature oligodendrocytes. We have also Myelination of axons in the vertebrate nervous system is identified a link between the cytoplasmic region of NG2 and essential for the fast propagation of action potentials. The multilamellar myelin sheath is a specialised, polarised, lipid- rich domain of the glial cell plasma membrane, synthesised by oligodendrocytes in the CNS and Schwann cells in the PNS. Loss of myelin, results in paralysis. Our aim is to define the molecules of glial precursor cells regulating the migration to and interaction with myelination-competent neurones and to elucidate the cell biological principles underlying the synthesis of myelin. The mechanism of sorting and compartmentation of proteins and lipids in myelinating glia, for example via lipid rafts, is also a central topic. These topics are additionally of clinical relevance in the context of de- and dysmyelinating diseases (e.g. Multiple Scle- Fig. 1. Stages in the life of an oligodendrocyte rosis), the migration of neural tumours and the missorting of glial proteins and lipids in the pathology of human disease. Recent work is also addressing the interaction of glial pro- the cytoskeleton which may play a role in cell and cell progenitor cells with neurones at synapses. cess movement and cell migration.

The AN2/NG2 Glycoprotein in Development and Disease Oligodendroglia sort GPI-anchored adhesion molecules We have recently shown that the AN2 glycoprotein is the associated with Signalling Complexes into lipid rafts in the mouse homologue of human and rat NG2. It is expressed by early phases of Glial-Axon recognition migratory oligodendroglial and Schwann cell precursors and In maturing oligodendrocytes, the glycosylphosphatidyli- is down-regulated as these cells mature. It is also expressed nositol-anchored proteins F3 and NCAM 120 associate with by synaptic glia and may play a role in regulating synpatic the intracellular tyrosine kinase Fyn and the myelin lipids activity and network properties. A subset of patients with cholesterol and glycosphingolipids in detergent-resistant the demyelinating disease Multiple Sclerosis, synthesise "rafts". The activity of Fyn is highest during myelination. 44 Jacqueline Trotter

These complexes may thus couple adhesion molecules to 5) Definition of the cellular sorting and transport processes signal transduction cascades inside the glial cell whose acti- utilised by oligodendrocytes to build up the domain vation stimulates the myelination programme. Ligation of structure of myelin. How and where in the cell are the such adhesion molecules by axonal ligands may thus induce different microdomains generated, leading ultimately to cytoskeletal changes leading to the wrapping of axons and the subdomains of myelin? What is the role of neuronal the laying down of the multilamellar sheath. We have shown contact in this process? that in oligodendrocytes Fyn associates with the microtubule associated protein Tau and also with Tubulin. Disrup- Selected Publications tion of the Fyn-Tau interaction in cultured oligodendrocytes [1] Krämer, E-M et al. (1999) J.Biol. Chem. 274, 29042-29049. inhibits process outgrowth. Rafts may be a site of signal- [2] Simons, M. et al. (2000) J. Cell Biol., 151, 143-154. transduction within the glial-axonal unit and serve to [3] Schneider, et al. (2001) J.Neurosci. 21, 920-933. polarise vesicle traffic towards the glial axonal contact site. [4] Klein, C. et al. (2002) J. Neurosci. 22: 698-707. [5] Stegmüller J. et al. (2003). J.Biol. Chem. 278: 3590-3598 The Sorting of Myelin Components in Oligodendrocytes The generation of the myelin sheath involves the seIective Structure of the group targeting to and exclusion of distinct proteins and lipids to Group leader Jacqueline Trotter the specialised subdomains of myelin: e.g. compact myelin, Senior scientist Eva-Maria Albers the adaxonal membrane and the paranodes. We are using Graduate students Iris Bobenhausen, Nivedita Chatterjee primary cultures of oligodendroglia to analyse the cell bio- Khalad Karram, Christine Winterstein logical principles underlying this sorting out of cellular pro- Technicians Liljia Niedens, Ulrike Stapf teins and lipids to generate myelin. We have shown that oligodendrocytes use lipid rafts to sort the main myelin pro- Contact tein, PLP into the forming sheath. Prof. Dr. Jacqueline Trotter Future Projects and Goals Molekulare Zellbiologie/Biologie für Mediziner Institut für Zoologie, Fachbereich Biologie 1) Elucidation of the adhesion molecules regulating the Johannes Gutenberg-Universität Mainz migration of glial progenitor cells and their connection Bentzelweg 3 to the cell cytoskeleton. In particular, the role of the 55099 Mainz AN2/NG2 proteoglycan in this process. A +49-(0)6131-3922879 E +49-(0)6131-3923840 K 2) What is the role of NG2+ glia at synapses: do neurons [email protected] express receptors for the glycoprotein? http://www.iak.uni-mainz.de http://www.nbio.uni-heidelberg.de/trotter 3) What is the role of the antibody against AN2 in the pathology of MS? Are specific regions of the molecule immunogenic in patients?

4) Analysis of the axon-glial interaction and signaltrans- Fig. 2. Migra- Oligodendrocytes tory oli- express the myelin duction: Definition of the signals required to initiate and godendrocyte lipid sulfatide and maintain myelination. The role of the src kinase mem- progenitor the cytoskeletal bers fyn and lyn expressed by glia in this process. What cells express protein Tau are the axonal and glial partner adhesion molecules? the AN2 gyl- What is the role of raft-associated cytoskeleton? coprotein

45 Research Profiles Control of peripheral nerve outgrowth We have worked with the four members of the neurotrophin in embryonic mouse development family, which includes nerve growth factor (NGF), brain- Kerry L. Tucker derived growth factor (BDNF), neurotrophin-3 Ph.D. 1997 Massachusetts Institute of Technology, Cambridge, (NT-3), and neurotrophin-4. Massachusetts Using recombinant neurotro- Post-doctoral work at the Max Planck Institute of Neurobiology and the phins and function-blocking Friedrich Miescher Institute antibodies to them, we were Group leader at the IZN as of 2003 able to demonstrate that NGF, NT-3 and BDNF play a Current Research crucial role in promoting the growth of nerves in the forelimb. As neurotrophins are not In the developing nervous system, newborn neurons elabo- expected to be the only molecules involved in this process, rate axonal processes that navigate complicated pathways we are extending these studies using three complementary and often travel long distances before they reach their tar- experimental approaches. get. Ultimately one would like to study this developmental process as it occurs in the organism. Ideal would be a means Time-lapse imaging to directly and non-invasively observe the behavior of outgrowing nerves in their native environment. To do this, we We are performing high-resolution imaging of nerve out- have engineered a mouse to express the enhanced green flu- growth into the embryonic limb, which is innervated by spi- orescent protein (EGFP), which produces an intense fluores- nal nerves derived from motor neurons of the ventral spinal cence signal upon light excitation. The gene encoding EGFP cord and sensory neurons of the dorsal root ganglia. We will was inserted into the mouse genome in such a way that employ a microscope set-up allowing for cultivation of expression is specific to neurons, and the levels of EGFP pro- embryo slices upon the microscope stage itself, with the use duced are high enough to clearly label the entire length of of a contained tissue-culture environment. We have begun outgrowing axons (see Figure 1). The tEGFP mouse line was our studies using the tEGFP mice, and with new lines derived used to establish an embryonic slice-culture method in from crosses between the tEGFP mice and mutants in two which we can perform time-lapse imaging of the peripheral gene families known to be important for early outgrowth of outgrowth of nerves of the spinal and cranial ganglia. spinal nerves, the neurotrophins and the semaphorins.

Reverse genetic analysis of nerve outgrowth Fig 1: 11.0 days post coitum We have developed a simple system for reliable expression of mouse embryo expressing EGFP genes of interest specifically in neurons, such that heterolo- from the Mtapt locus, visualized gous cDNAs are switched on shortly after the birth of the through epi-fluorescence illumi- nation. All spinal (*) and cranial transgenic neurons. This allows for overexpression of normal (arrowheads) ganglia are ex- and mutant forms of genes of relevance to axonal extension, pressing the marker, and out- to test for their effects upon axonal growth in vitro and in growing nerves are clearly the developing mouse embryo. This system is also being labeled (arrows). e = developing engineered to allow for the inducible activation of genes of eye interest within neurons, allowing for temporal as well as special specificity.

46 Kerry L. Tucker

ENU mutagenesis Selected Publications

The tEGFP mouse allows the direct visualization of all nerves [1] Tucker, K. L., Meyer, M., and Barde, Y.-A. (2001) Nature Neuroscience derived from the cranial and spinal ganglia, in a developmen- 4: 29-37. tal time-frame extending from early neurogenesis to late [2] Yamashita, T., Tucker, K. L., and Barde, Y.-A. (1999) Neuron 24: 585- stages of gestation. This feature opens the possibility of an 593. examination of general defects in this complicated process, [3] Heins, N., et al. (2002) Nature Neuroscience 5, 308-315. through the induction of random mutations via chemical [4] Tucker, K. L. (2001) Neuron 30: 649-652. mutagens such as ethyl-nitroso-urea (ENU). To uncover [5] Wernig, M., et al. (2002) Journal of Neuroscience Research 69, 918- recessive mutations, mutagenized males are mated with their 924. daughters, and litters of embryos examined at specific time points during embryogenesis. The entire peripheral nervous Structure of the group system is screened for defects in gangliogenesis and axonal Group leader Kerry Tucker outgrowth through visual inspection of embryos, using fluo- Technician Catherine Bradford rescent microscopy. We have identified three initial mutations that bear defects in outgrowth of various cranial Contact ganglia and in the development of the telenecephalon (see Figure 2). Dr. Kerry Tucker Friedrich Miescher Institute for Biomedical Research The uncovered mutants will be further analyzed through his- WRO 1066.4.10 tochemical analysis, in vitro culturing of slices from mutant CH-4058 Basel embryos, and, ultimately, positional cloning of the mutated Switzerland gene in question. Where relevant, both engineered and A +41-(0) 61 697 6954 ENU-induced mutants will be imaged in our slice culture sys- E +41-(0) 61 697 3976 tem, to better ascertain the nature of the defects. These K [email protected] approaches are expected to give us new insights into the http:// www.izn.uni-heidelberg.de/ wiring of the nervous system, as it develops in the animal http://www.sfb488.uni-hd.de/ itself.

Fig. 2: Mutant E5 showing ectopic cells (arrow, right) in telecephalon of a mid-gestation embryo. Note lack of such cells in wild type (WT) telencephalon. (arrowhead = ocular branch of trigeminal nerve; e = eye)

47 Research Profiles TGF-ßs, FGFs and neurotrophins in by itself or in synergy with other factors, in suppressing neural development and functions neuronal and promoting endocrine features in SA pro- Klaus Unsicker genitors.

MD 1968 University of Kiel, Germany Development and Postdoctoral work at Universities of Lund, Melbourne, and UC London, maintenance of the neural Research Fellow UC San Diego 1983/84, NIH/NCI Bethesda 1989/ circuitry that links CNS and 90, Professor University of Marburg 1978-92, Professor of Anatomy & Cell Biology, Neuroanatomy, IZN Heidelberg, since 1992 peripheral portions of the sympathetic nervous system Current Research Sympathetic neurons and chromaffin cells are innervated by preganglionic sympathetic Development of distinct cell phenotypes, neuron survival, neurons (PSN; Fig. 1) that are located in the spinal cord and network formation, and responses to lesions in the nervous develop from the same precursor pool as motoneurons. In system depend on the concerted actions of numerous, contrast to the abundant information available for factors largely multifunctional growth factors. Ongoing projects in that affect motoneuron development, very little is known on the group include the following: (1) specification of neural PSN promoting factors. Using knockout mice we have estab- crest (NC) derived neuronal and neuroendocrine cells and lished that the LIFRß and neurotrophin-4, but not FGF-2, their integration into neural circuitries, (2) functional char- are important for embryonic and postnatal, respectively, acterization and signaling of a novel member of the TGF-ßs, development of PSN neurons. GDF-15, (3) significance of neurotrophin signaling for the development and maintenance of CNS aminergic systems, Functional characterization and signaling of a novel and (4) roles of FGFs and TGF-ßs in neuronal and astroglial member of the TGF-ßs, GDF-15 functions. GDF-15 is a novel, distant member of the TGF-ßs with wide The NC as a paradigm for studying generation of cell distribution in the CNS. As a trophic factor for midbrain dopaminergic neurons in vitro and in vivo it is at least as diversity The NC gives rise to diverse neuronal, endocrine, and mes- enchymal cell types and, hence, is an excellent model for exploring mechanisms involved in the generation of cell diversity. We focus on the sympathoadrenal (SA) cell lineage, which gives rise to sympathetic neurons and neuroendocrine chromaffin cells. We have found that glucocorticoid signaling, contrary to a previous hypothesis, is not essential or sufficient for generating chromaffin cells. We are currently studying the roles of BMP-4 and transcription factors in the specification of chromaffin as opposed to neuronal cells using loss- and gain-of-function paradigms. The bhlh transcription factor MASH-1 is important for the development of a major subpopulation of chromaffin cells. BMP-4 is Fig. 1 Retrogradely traced IML neuronal cell bodies and processes highly and persistently expressed in all locations, where (marked by arrowheads) extending towards the central canal (CC) of the spinal cord. Bar: 40 µm. By A. Schober chromaffin cells develop, suggesting that it may play a role, 48 Klaus Unsicker potent as GDNF. GDF-15 is prominently upregulated in ffin cells, respectively, may phenotypically segregate prior to lesioned neurons suggesting functions related to executing reaching their final target sites. We are working on the iden- survival or death programs. On cerebellar granule neurons tification of the GDF-15 receptor and hope to obtain addi- GDF-15 exerts its survival promoting effect through activa- tional cues as to its functions from the current analysis of tion of the PI3K/Akt/GSK-3 pathway. A GDF-15 knockout the GDF-15 knockout. We will expand on the use of trans- mouse has been generated and is currently analyzed. genic animal models to understand the roles of FGFs and TGF-ßs not only in development, but also in the context of Significance of neurotrophin signaling for the lesions with clinical relevance. development and maintenance of CNS aminergic systems BDNF, NT-3, and NT-4 have been shown to be important Selected Publications regulators of the development and plasticity of the dopam- [1] Finotto, S., et al. (1999) Development 126, 2935-2944. inergic and serotonergic systems. We use aged trkB and trkC [2] Huber, K., et al. (2002) Development 129, 4729-4738. heterozygous knockout mice to analyze functional deficits [3] Krieglstein, K., et al. (2000) Nature Neuroscience 3, 1085-1090. related to these aminergic systems. [4] Roosen, A., et al. (2001) Journal of Neuroscience 21, 3073-3084. [5] Peterziel, H., et al. (2002) Journal of Cell Biology 159. 157-167. Roles of FGFs and TGF-ßs in neuronal and astroglial functions Structure of the group We are studying the roles of FGF-2, -5, -9, and TGF-ß2 and Group leader Klaus Unsicker -ß3 in the regulation of neuronal and astroglial development Postdoctoral fellows Oliver v. Bohlen, Katrin Huber and functions in the adult. Using in vitro approaches and Heike Peterziel, Bernhard Reuss knockout mice we have found that FGFs regulate astroglial Katharina Schindowski, Andreas Schober differentiation, gap junction communication, and blood- Jens Strelau brain-barrier permeability in a region-specific fashion Graduate students Armin Goralczyk, Antonio Garreta Rufus, (Fig. 2). Concerning TGF-ßs we focus on the molecular Aylin Franke, Marion Hof, Stephan Oberle bases of their synergistic roles with neurotrophins, GDNF, Corina Popovici, Srinivasa Subramaniam and FGF-2 in the regulation of neuron survival. Technicians Angelika Brüntgens, Gerald Bendner, Barbara Brühl, Jutta Fey, Richard Hertel Fig. 2 GFAP-immuno- Ursula Hinz, Martina Scharpff, reactive astrocytes Marion Schmitt, Elisabeth Delius-Specht and albumin extravasation in the cortex of FGF2/FGF5 deficient Contact mouse mutants and wildtype littermates. Prof. Dr. Klaus Unsicker Bars: 40µm (a, b) and IZN, Institut für Anatomie und Zellbiologie, 20 µm (c, d). By B. Abt. Neuroanatomie Reuss Universität Heidelberg Im Neuenheimer Feld 307 Future Projects and Goals 69120 Heidelberg Our long-term goal is to understand the hierarchies and Germany A interdependencies of molecules involved in the generation of +49-(0)6221 - 54 8228 E cellular heterogeniety and cell-cell communication in the +49-(0)6221 - 54 5604 nervous system. Current work in the NC project suggests K [email protected] that SA progenitors destined to become neurons or chroma- http://www.anatomie.uni-hd.de/ 49 Research Profiles Inhibitory ion channels are the diverse expression patterns generated"? We William Wisden study these problems in the cerebellum, a brain region PhD 1989 Cambridge University, UK that controls motor move- Postdoctoral work at ZMBH, University of Heidelberg (1990-1992) ments and memories. Our Group leader at the MRC Laboratory of Molecular Biology, Cambridge, studies will help us under- UK (1993-2000) stand more complicated situ- Group leader at the Dept. of Clinical Neurobiology, University Hospital ations in other brain regions. of Neurology, Heidelberg since 2001 Cerebellar granule cells form Current Research part of a circuit that learns and executes motor memo- Brain function depends on balancing synaptic excitation and ries. For example, riding a bicycle or playing the piano both inhibition. γ−Aminobutyric acid (GABA), the most important require the cerebellum. In mice this circuit is well-suited to inhibitory neurotransmitter used for this, works at GABAA genetic dissection; mutations can be readout as changes in receptors. These are heteromeric transmitter-gated chloride motor skill. Why do different synapses in this circuit use dif- channels. The GABAA receptor subunit genes (α1-6, β1-3, ferent GABAA receptor subtypes? This is what we want to γ 1-3, δ, ε, θ, ρ and π) are differentially transcribed, and find out. the subunits assemble combinatorially into heteromeric pen- Past work: α6 subunit gene knockout tamers. Defects in GABAA receptors cause diseases such as epilepsy. GABA receptors are also targets for important Granule cells express six subunit genes (α1, α6, β2, β3, A γ2 δ) , drugs: benzodiazepines, barbiturates and steroids. and and make at least three subtypes of GABAA receptor. We made a mouse line with an α6 gene disruption. Key questions: "How many receptor subtypes are there?", Unlike the other subunit genes, α6 gene expression is "What are these different receptor subtypes for"? and "How restricted to cerebellar granule cells - this knock-out affected only the cerebellum. Actually, the mice have a double subunit knockout in the cerebellum: in addition to the α6 loss, δ protein also completely disappears from the granule cell surface. Thus α6 and δ make a specific type of GABAA receptor. Surprisingly, in spite of large losses of GABAA receptors from α6 -/- granule cells, the mice are normal on cerebellar-related motor tasks.

The α6δ−containing receptor is specifically extrasynaptic. Granule cells are bathed in GABA. This GABA bath is generated by transmitter diffusing from the GABAergic interneuron-granule cell synapse. As shown by Cull-Candy's group at UCL in London, GABA continuously activates extrasynaptic GABAA receptors as a tonic background conductance. The tonic current likely modulates the dynamic range over which Expression of the α1 and α6 subunit genes in the cerebellum, as seen granule cells fire action potentials. The α6δ-containing by in situ hybridization. 50 William Wisden

GABAA receptors are directly involved in this process: in Summary α6 -/- granule cells, the background inhibition is completely My group researches the transmitter receptors (GABA ) gone. This should have severe consequences, but there has A used to inhibit neuronal firing in the brain. These receptors + been a compensation: a K leak conductance has been up- have tremendous diversity; we want to understand why. As a regulated. This conductance may do the same job as the simple system, we use cerebellar granule cells. These cells extrasynaptic α6δ-containing GABAA receptors, making it provide a mini-world of GABAA receptor complexity. Mouse harder for excitatory inputs to initiate action potentials. mutants with specifically engineered and/or deleted GABAA receptor genes in granule cells make it possible to under- + Future work: K channel expression stand the rich diversity of GABAA receptor in complex brain The α6 knockout mice have compensated for the α6 and δ regions such as the hippocampus or neocortex. protein loss by upregulating the expression of a potassium channel gene. The conventional knockout did not tell us Selected Publications α directly the function of the 6 gene; on the other hand, it [1] Brickley SG, Revilla V, Cull-Candy SG, Wisden W and Farrant M, illustrated the remarkable abilities of biological systems to (2001). Nature 409, 88-92. make do with alternative strategies. We are currently identi- [2] Wisden, W. and Stephens, D.N. (1999). Nature 401, 751-752. fying the potassium channel responsible and studying how [3] Mellor JR, Merlo D, Jones A, Wisden W and Randall AD (1998) J. the change in its expression has occurred. Neurosci. 18, 2822-2833. [4] Bahn S, Jones A, and Wisden W (1997) Proc. Natl. Acad. Sci. USA 94, 9417-9421. Future work: further dissecting GABAA receptor [5] Jones, A., Korpi, E.R., McKernan, R.M., Pelz, R., Nusser, Z., Mäkelä, R., diversity in cerebellar granule cells. Mellor, J.R., Pollard, S., Bahn, S., Stephenson, F.A., Randall, A.D., Sieghart, W., Somogyi, P., Smith, A.J.H. and Wisden, W. (1997). J. In addition to α6's extrasynaptic location, this subunit colo- Neurosci. 17, 1350-1362. calizes with the α1, β2/ 3 and γ2 subunits in the synapse. α1 α Why are both the and 6 subunits needed at the syn- Structure of the group apse? We will ablate α1 and γ2 subunit gene expression specifically in cerebellar granule cells, and without affecting the Group leader William Wisden rest of the brain. To do this we are using Cre recombinase Postdoctoral fellows Isabel Aller, Peer Wulff (see next section). Graduate students Ayla Arslan, Christina Sandu Undergraduate student Thomas Götz Future work: cerebellar granule cell-specific ablation of genes using Cre recombinase. Contact We have mice lines with Cre recombinase expressed from the Dr. William Wisden α6 gene (Aller, Jones, Merlo, Wisden, unpublished). This IZN, Dept. of Clinical Neurobiology gives Cre expression in adult cerebellar granule cells. These University of Heidelberg lines will allow specific lesions of other genes in cerebellar Im Neuenheimer Feld 364 69120 Heidelberg, Germany granule cells, including K+ channel subunit genes (see A +49-(0)6221-56 2403 above), without affecting the rest of the brain. The Cre mice E are crossed with other mouse lines with "floxed" genes - +49-(0)6221-56 1397 K genes with lox P sites (the recognition sites for Cre recombi- [email protected] nase) flanking key exons. This causes disruption of the target http://klinnbio.uni-hd.de/Wisden-e gene just in cerebellar granule cells.

Selected Research Profiles of Outer Circle Members Research Profiles - Outer Circle Bernd W. Böttiger

Experimental cerebral ischaemia Future Projects and Goals The goal of these investigations is Bernd W. Böttiger to precisely characterize the mechanisms involved in delayed MD 1986, University of Heidelberg neuronal death so as to directly 1994 - 1996, Max-Planck-Institute for Neurological Research, Cologne, transfer these results to the clini- Germany cal setting and improve neurologi- 1996, 1999, Ischemia Research and Education Foundation, San cal outcome after cardiac arrest in Francisco, U.S.A. humans. Subsequently, different novel therapeutic strategies that 1997, Associate Professor of Anaesthesiology, Group Leader Molecular inhibit the apoptotic cascade Biology Laboratory upstream and/or downstream will 1998 - 2001, Visiting Professor at the Universities of Stanford, Duke, be tested. All these therapeutic Chicago and Pittsburgh, USA strategies (neurotrophins, inhibi- Current position: Co-Chair of the Department of Anaesthesiology, tion of apoptosis-inducing death receptors and caspase inhibitors) University of Heidelberg can be tested in our well-established cardiac arrest models in rats and mice. Current Experimental Research A.) Improvement in neurological outcome after cardiac Selected Publications arrest [1] Böttiger BW et al. J Cereb Blood Flow Metab (1998) 18:1077-87 Cerebral damage following cardiocirculatory arrest is a major public [2] Böttiger BW et al. Mol Brain Res (1999) 65:135-42 health care issue. To date no specific treatment options (with the [3] Böttiger BW et al. Lancet (2001) 357:1583-5 exception of mild hypothermia and thrombolysis in selected [4] Böttiger BW et al. Circulation (2001) 103:2694-8 patients) are available to improve neurological outcome following [5] Safar P et al. Crit Care Med (2001) 30(4 Suppl):S140-4 cardiocirculatory arrest. Therefore, innovative basic and clinical research is absolutely essential. Our investigations are based on the hypothesis that apoptosis (programmed cell death) might play an important role in these mechanisms. Using a unique murine and Structure of the group rat model of global cerebral ischaemia after cardiac arrest, we are Group Leader Bernd W. Böttiger studying the effects of anti-apoptotic interventions, for example Postdoctoral fellows Jakub Krumnikl, Erik Popp, Peter the investigation of transgenic animals overexpressing anti-apop- Teschendorf, Peter Vogel totic proteins such as p35, CrmA, Bcl-2, Bcl-XL or the intracere- Graduate student Mia Kim Technicians Roland Galmbacher, Klaus Stefan broventricular administration of synthetic caspase inhibitors (z- DEVD-FMK). Contact B.) Transient focal cerebral ischaemia in a transgenic Bernd W. Böttiger, MD, DEAA murine model Associate Professor of Anaesthesiology Delayed neuronal death is also a major cause of the high morbidity A +49 6221 566351 and mortality associated with stroke (focal cerebral ischaemia). In E +49 6221 565345 collaboration with the Departments of Physiology and Neurology K [email protected] we are investigating the efficacy of these anti-apoptotic proteins in http://www.med.uni-heidelberg.de/anaes/groups/boettiger002.htm preventing delayed neuronal death after focal cerebral ischaemia in transgenic mice (see above).

54 Andreas Draguhn

Inhibitory synapses and network Future Projects and Goals oscillations We want to examine

• examine GABA-metabolism Andreas Draguhn as a general mechanism of synaptic plasticity; MD 1991 , U n i v e r s i t y of Heidelberg Postdoctoral work at Köln University, Humboldt University (Charité, • compare the role of reverse Berlin),University of Birmingham (UK). GABA-uptake versus Since 2002 Professor of Physiology, Medical Faculty, Heidelberg vesicular GABA-release in immature brain tissue; University. • characterise alterations of Current Research GABAergic synapses and circuits in chronic epilepsy; We examine electrical functions of the mammalian brain at the levels of single inhibitory synapses and of neuronal networks with • analyse the modulation of GABA release by presynaptic coordinated multicellular activity. Both subjects are strongly inter- ionotropic GABA-receptors; related through the dominant role of inhibitory interneurons in the • study the role of GABAergic interneurons in high-frequency synchronization of network oscillations as well as in pathological network oscillations; network activity (epilepsy). • establish the nature and subcellular localization of hippocampal gap junctions which are involved in ripples; Inhibitory synapses of higher mammalian brain nuclei act by the storage and release of GABA (γ-aminobutyric acid). While much is • investigate the potential role of ripples in memory formation at known about structure and function of GABA receptors, we focus a mechanistic level in vitro. on two additional elements: GABA-uptake and GABA-metabolism. We have analysed the functional maturation, ontogenetic expres- Selected Publications sion and local specificity of the GABA transporter GAT-1 in the [1] Maier, N. et al. (2002) J Physiol. (London) 541, 521-528. rodent hippocampus. At present, we analyse the regulation of [2] Frahm, C. and Draguhn, A. (2001) Brain Res Dev Brain Res. 14, 1-13. inhibitory synaptic efficacy through GABA-metabolism. Our results [3] Engel, D. et al., (2001) J. Physiol. (London) 535, 473-482. indicate that alterations in GABA-production are an autonomous [4] Frahm, C. et al. (2001) Neuroreport 12, 1593-1596. mechanism of synaptic plasticity. All projects dealing with GABAer- [5] Draguhn, A. et al. (1998) Nature 394, 189-192. gic transmission are also applied to models of epilepsy. Structure of the group High-frequency network oscillations at ~200 Hz ("ripples") are a characteristic pattern of hippocampal activity during slow-wave Group leader Andreas Draguhn sleep and have been implicated in long-term memory formation. We Postdoctoral fellows Volker Nimmrich, N.N. analyse the mechanisms of such network oscillations in brain slices Graduate students Nikolai Axmacher, Kristin Hartmann, in vitro. We have found that electrical synapses (gap junctions) are Nikolaus Maier, Frank Stief needed for neuronal synchronization at this high frequency. In Technician Petra Rook addition, most hippocampal projection cells receive strong GABAergic inhibition during ripples. We assume that inhibitory Contact interneurons contribute to the coordination of fast rhythmic activ- Prof. Dr. Andreas Draguhn ity and may be the key to the selection of cells which do participate Institut für Physiologie und Pathophysiologie in ripples from those which stay silent. Universität Heidelberg Im Neuenheimer Feld 326 69120 Heidelberg, Germany A +49 -(0) 6221 - 54 4056, E +49-(0) 6221 - 54 4049 K [email protected] 55 Herta Flor

Learning and neuronal plasticity Future Projects and Goals In close cooperation with other Herta Flor research groups, we are launching a collaborative research grant ini- 1983 P h . D . i n Ps ychology, University of Tübingen tiative on learning and plasticity 1983-1987 Post-Doctoral and assistant professor positions at Yale underlying psychopathology. This University, and at the University of Pittsburgh, USA research lies at the intersection of 1987-1993 DFG-Scholarship & Heisenberg Fellow (DFG), University of neurobiology, experimental and clinical psychology and biological Tübingen psychiatry and is unique in bring- 1993-2000 Professor (C4) for Clinical Psycholoy & ing together similar research Somatopsychology Humboldt University, Berlin, since 2000 Professor designs on different levels of (C4) of Neuropsychology, Central Institute of Mental Health, analysis (molecular, behavioral, Mannheim clinical) of learning and plasticity. Rather than taking a nosological approach which leads to the prob- Current Research lem of overlapping psychopathological characteristics and examin- At the core of our research lies the interaction between brain and ing the neurobehavioral and molecular mechanisms of individual behavior. In particular, we are interested in elucidating the neuronal disorders, this planned initiative seeks to determine similarities and correlates of learning and memory. Our research involves measures differences of the underlying mechanisms of learning and neural of cortical activity such as EEG and MEG, functional imaging tech- plasticity across a variety of disorders. We will pursue basic associa- niques, measures of peripheral phsyiological activity (EMG, skin tive and non-associative learning mechanisms and their neuronal conductance, heart rate) as well as markers of endocrinological correlates which are fundamental for the understanding of disor- activity (e.g., cortisol). ders as e.g., post-traumatic stress disorder, social phobia, depression). A first line of research is focusing on neuronal plasticity in the somatosensory system and its contribution to pain memory. Using Selected Publications a cross-sectional approach, the relationship between neuronal [1] Birbaumer et al., (1999). Nature, 398, 297-298. reorganization within the somatosensory system and painful and [2] Flor et al. (2001). Lancet, 357, 1763-1764. non-painful phantom phenomena is assessed in both upper and [3] Hermann et al. (2002). Biological Psychiatry, 52, 328-337. [4] Karl et al. (2001). Journal of Neuroscience, 21, 3609-3618. lower limb amputees using EEG and fMRI measurements. Using a [5] Lotze et al. (1999). Nature Neuroscience, 2, 501-502. prospective approach, the role of the glutamatergic and GABAergic transmitter systems in modulating neuronal plasticity is investigated Structure of the group in amputees by using different pharmacologic blocking agents. Group leader Herta Flor Postdoctoral fellows Eugen Diesch, Carsten Diener, Christiane A second line of research concerns the contribution of neuronal Hermann, Christoph Schneider plasticity in the auditory system to the development and mainte- Graduate students Christoph Christmann, Martin Diers, Johanna nance of tinnitus symptoms. After having demonstrated that tinni- Hohmeister, Caroline Köppe, Jaana Markela- tus is associated with a reorganization of the tonotopic map in the Lerenc, Claudia Rolko, Maren Struve, Michèle primary auditory cortex, we currently determine the effectiveness Wessa, Katrin Zohsel Technicians Michael Rehm, Heike Schmidt of an auditory discimination training in improving Tinnitus severity and impairment. A third line of research targets the development Contact and maintenance of fear memories and their neuronal correlates. Prof. Herta Flor Recently, we found first evidence that a hypoactive fronto-limbic Lehrstuhl für Neuropsychologie an der Universität Heidelberg fear circuitry may account for the dissocial behavior in sociopaths. Zentralinstitut für Seelische Gesundheit By contrast, the excessive social fears in social phobics seem to J5, 68159 Mannheim, Germany reflect a hyperactive fronto-limbic circuit that can easily be acti- A +49-(0) 621 - 1703 922, E +49-(0) 621 - 1703 932 vated even by neutral and per se non-threatening social cues. K [email protected], http://www.zi-mannheim.de/orga.htm 56 Rainer Friedrich Function and development of olfactory neural circuits

Rainer Friedrich

PhD 1998 Max-Planck-Institute for Dev.Biol./University Tübingen, Tübingen, Germany Postdoctoral work at Caltech, Pasadena, CA, USA at the Max-Planck-Institute for Medical Research, Heidelberg, Germany, since 2001

Current Research We study how complex odor information is processed by dynamic neural circuits in the brain, and how these circuits emerge during development. In the first olfactory processing center, the olfactory bulb (OB), each odor activates a particular combination of input Selected Publications channels (the olfactory glomeruli). The ciruitry within the OB then [1] Friedrich RW, Laurent G (2001) Science 291: 889-894 dynamically transforms these activity patterns. We are currently [2] Friedrich RW, Stopfer M (2001) Curr. Opin. Neurobiol. 11: 468-474 investigating the function and the cellular bases of these dynamic [3] Friedrich RW, Korsching S (1998) J. Neurosci. 18: 9977-9988 computations, using the zebrafish and mouse as model systems. [4] Nicolson T, Rüsch A, Friedrich RW, Granato M, Ruppersberg JP, Moreover, in zebrafish we are studying the function of the embry- Nüsslein-Volhard C (1998) Neuron 20: 271-283 onic olfactory system and the transition from the embryonic to the [5] Friedrich RW, Korsching SI (1997) Neuron 18: 737-752 adult brain function.

In particular, we use optical imaging methods (fast CCD-cameras, Structure of the group 2-photon microscopy) to record the acvitity of single neurons and neuronal ensembles in the intact brain. For such optical Group leader Rainer Friedrich approaches, the transparent zebrafish embryo is ideal. With mod- Postdoctoral fellows Christopher Habermann, Jun Li , ern optical methods such as 2-photon microscopy it is also possi- Hartwig Spors ble to image living neurons in the mouse. Optical techniques are Graduate students Julia Mack, Rico Tabor, Emre Yaksi combined with electrophysiology, embryology and molecular biol- Technicians Heike Brinkmann, Uschi Buhre ogy (transgenics) to analyze the development and function of a complex neural network in the intact animal.

Future Projects and Goals Contact A research focus in the future will be the functional development of Dr. Rainer Friedrich Abteilung für biomedizinische Optik the neuronal circuitry in the OB. Using 2-photon microscopy, we Max-Planck-Institut für medizinische Forschung will follow the development of individual neurons through develop- Jahnstr. 29 ment and record their odor response properties. In addition, we are 69120 Heidelberg starting to use transgenic approaches for optical recording of neu- Germany ronal activity, and to exploit the large collection of zebrafish A +49-(0) 6221- 486 408 mutants. In the adult olfactory system of zebrafish and mouse, we E +49-(0) 6221 - 486 325 investigate the relationship between spatial and temporal structure K [email protected] in odor-evoked activity patterns using high-speed voltage-sensitive http://wbmo.mpimf-heidelberg.mpg.de/~fried/index.html dye imaging, 2-photon microscopy, and electrophysiology.

57 Harald Hutter

Genetics of axon guidance in C. elegans in all neuronally expressed members of the IgCAM and Cadherin families moving away from the sin- Harald Hutter gle gene analysis to study entire gene families and their interac- PhD 1995 Max-Planck-Institute for Biochemistry, Martinsried, Germany tions. In addition we will use RNAi Postdoctoral work at the Johns Hopkins University, Baltimore, USA screens for axon guidance genes Junior group leader at the Max-Planck-Institute for Medical Research, with special mutants isolated in Heidelberg, since April 1999 our lab, which are hypersensitive to RNAi in the nervous system. Current Research Deletion alleles in candidate genes coming form these screens The wiring of the nervous system is established during embryogen- will be generated and studied fur- esis when all the neurons send out processes which eventually con- ther. nect to their target cells to form neuronal circuits. The large number of neurons involved and the complex pattern of neurite outgrowth makes this a formidable navigational problem. We use genetic and reverse genetic approaches in the nematode Cae- Selected Publications norhabditis elegans to identify key molecules important for axon [1] Hutter H., et al. (2000) Science 287: 989-994. navigation. In genetic screens for mutants with axonal outgrowth [2] Hutter, H. (2000) Microscopy Research and Technique 48: 47-54. defects we have identified a number of novel genes involved in various aspects of axonal pathfinding. Two of the genes identified so far turned out to be transcription factors affecting late aspects of neuronal differentiation. These as well as several other genes are Structure of the group studied in more detail at the moment. Group leader Harald Hutter Postdoctoral fellow Irene Wacker In a complementary approach we use the sequence information Graduate students Parag Kinge, Christina Schmid, generated by the C. elegans genome sequencing consortium to Valentin Schwarz search for candidate axon guidance genes, which are then studied Technicians Suse Zobeley, Ilse Wunderlich using gene knock-out strategies.

Future Projects and Goals The transcription factors identified in the genetic screens provide Contact entry points for further analysis. Some of the target genes might Dr. Harald Hutter directly control axon navigation and we will use different methods Max-Planck-Institut für medizinische Forschung to identify at least some of them. Enhancer or suppressor screens Jahnstr. 29 will be used to identify novel genes interacting genetically with the 69120 Heidelberg Germany genes identified so far. Further genetic screens are in progress and A +49-(0)6221-486-268 (office) /-246 (lab) are likely to identify more of the genes essential for correct axon E +49-(0)6221-486-437 outgrowth. K [email protected] http://www.mpimf-heidelberg.mpg.de/ewgdn Cell adhesion molecules are known to play an important role in axon outgrowth. The largest families are IgCAMs and cadherins and the C. elegans sequencing project has identified all the members of these families. We have established a library of mutagenized C. elegans animals, which can be screened to identify deletions in candidate genes. We have started to use this library to isolate mutations

58 Marika Kiessling

Molecular basis of cerebral ischemia and projects of this research program aim at the identification of differ- ischemic preconditioning entially expressed proteins involved in the induction of an Marika Kiessling ischemia-tolerant state, since ischemic translational inhibition MD 1979, University of Freiburg, Germany has a profound effect on the Postdoctoral work at the University of Freiburg, Germany expression pattern of proteins Research Fellow Cornell University Medical College, Department of encoded by inducible genes. Neurology, New York, USA, 1983/84 Therefore, analyses will focus on Professor, University of the Saarland, Germany, 1988/89 the protein level using proteomics Medical Director of the Department of Neuropathology, IZN, University and subsequent expression stud- of Heidelberg, since 1990 ies of identified target proteins by molecular biological and in situ techniques. Current Research According to current concepts, excitotoxic activation of glutamate receptors is thought to play a pivotal role in the molecular patho- Selected Publications genesis of postischemic delayed neuronal death (DND). This concept has recently been extended to competing genetic programs [1] Schäbitz W.R. et al. (2000) Stroke 31, 2212-2217 that promote neuronal survival or death, respectively. Moreover, [2] Sommer C. et al. (2000) Brain Res 872, 172-180 there is compelling evidence for an impact on the brain's response [3] Roth S.U. et al. (2001) Brain Pathol 11, 169-181 to ischemia by endogenous or exogenous induction of an ischemia- [4] Sommer C. and Kiessling M. (2002) Stroke 33, 1093-1100 tolerant state. In particular, postischemic DND of vulnerable sub- [5] Sommer C. et al. (2002) Stroke 33, 1698-1705 sets of neurons can be prevented by ischemic preconditioning (IPC) with a sublethal noxious stimulus prior to an otherwise lethal period of brain ischemia. Structure of the group Group leader Marika Kiessling Current research focuses on molecular mechanisms that are critically involved in the acquisition of a neuroprotective state. Using Postdoctoral fellows Stephanie U. Roth, Clemens Sommer, rodent models of temporary global and focal brain ischemia, we Saida Zoubaa analyzed the regulation of neurotransmitter receptors with and Graduate students Alexander Fahrner, Krisztian Kapinya, without ischemia tolerance induction. We found (1) a differential Emre Tanay expression of ionotropic and metabotropic glutamate receptor sub- Technicians Antje Habel, Diana Jäger types and (2) a postischemic upregulation of GABAA receptor activity, indicating that a relative shift between inhibitory and excitatory neurotransmission may promote survival of vulnerable neu- Contact ronal subpopulations in the hippocampus (after global ischemia) and in the cortical penumbra (after experimental stroke, respec- Prof. Dr. Marika Kiessling Institut für Neuropathologie tively). Universität Heidelberg Im Neuenheimer Feld 220 Future Projects and Goals 69120 Heidelberg, Germany The understanding of molecular mechanisms that confer neuropro- A +49-(0) 6221 - 56-2603 E tection may increasingly determine clinical outcome after stroke +49-(0) 6221 - 56 4566 K and help to define new therapeutic strategies. There is intriguing [email protected] evidence that IPC also occurs in humans. This has raised considerable enthusiasm but calls for intense further basic research. Future

59 Joachim Kirsch

Ontogeny, stabilization and functional Future Projects and Goals adaptation of postsynaptic membrane We shall continue to identify the molecular components of specializations postsynaptic membrane specializations of both excitatory and Joachim Kirsch inhibitory synapses. These projects will be performed using 1987 Dr. med University of Bonn molecular biological approaches 1987-1991 Post doc, Weizmann-Institute and DKFZ Heidelberg and proteomics. Based on our 1991 -1998 Research Scientist, Heisenberg-Fellow, Schilling endowed studies on polypeptides provid- Professorship, Dept. Neurochemistry, MPI for Brain Research, Frankfurt ing the structural scaffold for the and Center of Morphology, University of Frankfurt organization of postsynaptic sig- 1995 Habilitation in Anatomy, University of Frankfurt naling complexes, we shall expand our research efforts on selected 1998-2002 Head of the Dept. of Anatomy & Cellular Neurobiology, components of individual signaling pathways. These may be University of Ulm involved in processes controlling receptor targeting, the regulation 2002- Head of the Dept. of Medical Cell Biology, Institute for Anatomy of gene transcription and the spatial regulation of translation in the and Cell Biology, University of Heidelberg somatodendritic cell compartment. The goal of our investigations is the identification of molecular mechanisms controling the Current Research dynamics and long-term plastic changes of synapses. Information processing in the CNS depends on fast neurotransmission, which is mediated by receptor proteins that are concentrated at distinct postsynaptic membrane specializations. The molecular Selected Publications mechanisms, which establish these specialized membrane domains [1] Kirsch, J. et al. , Nature (1998) 317, 717-720 during synaptogenesis and determine the positions, size and pack- [2] Sabatini, D. et al., Science (1999), 284, 1161-1164 ing densities of neurotransmitter receptor clusters, are poorly [3] Kins, S., et al., Nature Neurosci. (2000), 3, 22-29 understood. Moreover, it is unclear, how specific neurotransmitter [4] Ramming, M. et al., PNAS (2000) 97, 10266-10271 receptors are targeted to appropriate postsynaptic sites. Receptor- [5] Fuhrmann J. et al. , J. Neurosci. (2002) 22, 5393-5402 associated proteins are assumed to play an important role in these processes. Thus, our recent work has focused on the identification Structure of the group and functional characterization of molecules and mechanisms, such as synaptic activity, regulating the surface distribution neurotrans- Group leader Joachim Kirsch mitter receptors. Furthermore, the postsynaptic membrane and the Postdoctoral fellows Jochen Kuhse, Ralph Nawrotzki, NN subsynaptic cell compartments are not only specialized for inter- Graduate students Christina Janista, Karl Knöpfle, Rainer cellular but also for intracellular signaling. Activation of this sub- Neugebauer, Henrico Schmidt, Petra Weber synaptic machinery, whose building elements include structural Technicians Ingeborg Vogel, NN components and signaling molecules such as neuronal nitric oxide synthase, calcium/calmodulin-dependent kinase II, receptor Contact tyrosine kinases and modulators of the activity of monomeric GTPases, is thought to mediate nuclear signaling and/or long-term Prof. Dr. Joachim Kirsch changes in synaptic efficacy. Therefore, processes changing the Institut für Anatomie und Zellbiologie Universität Heidelberg molecular composition of the subsynaptic signaling machinery may Im Neuenheimer Feld 307 contribute to the long-term regulation of synaptic efficacy. Based 69120 Heidelberg, Germany on these considerations we have investigated the molecular com- A +49-(0) 6221 - 54 86256, E +49-(0) 6221 - 54 84952 positions of distinct types of receptor-associated subsynaptic pro- K [email protected] tein complexes and could identify several components of http://www.anatomie.uni-hd.de secondary signaling pathways. 60 Ulrich Misgeld

nals are tonically active and shift Plasticity of GABAA receptor mediated nigral inhibition from intrinsic to inhibition extrinsic. Tonically active cannab- inoid CB1 receptors have the Ulrich Misgeld opposite effect. A strong depo- larisation of GABAergic or MD 1968, University of Heidelberg dopaminergic neurons releases Training in Neurology /Psychiatry endocannabinoids, whereas a Postdoctoral work at MPI for Brain Research, Frankfurt/M., change of activity in dopaminer- Departments of Neurology and Pharmacology, UC Los Angeles, gic neurons by disinhibition California, MPI for Psychiatry, Dept. Neurophysiology, Munich enhances the D1 tone. Professor of Physiology, University of Heidelberg, since 1990 Future Projects and Goals Current Research Major goals of our work will be to study the role of GABA and of growth factors in the maturation of GABA inhibits brain neurons by activation of postsynaptic Cl- chan- KCC2 function and of GABAergic synapses. We pay special atten- nels, the GABAA receptors. Membrane potential changes resulting tion to the development of GABA responses in substantia nigra. from Cl- channel activation are variable, and there is a developmen- With respect to retrograde signaling, we will study the interaction tal change in the GABA response from depolarizing to hyperpolariz- of D1 and CB1 receptors in regulating extrinsic inhibition in substantia nigra. ing. Activation of inwardly rectifying K+ channels through the metabotropic GABA receptor induces also postsynaptic hyperpo- B Selected Publications larization. Our work focuses (1) on inhibition in weaver mice in [1] Yanovsky, Y. and Misgeld, U. (2002) Epilepsy Research, in press. which, due to the mutation of Kir 3.2, GABAB receptors do not [2] Kelsch, W., et al. (2001) J. Neurosci. 21, 8339-8347. + activate K channels, (2) the role of the neuronal cation-anion [3] Jarolimek, W., et al. (1999) J. Neurosci. 19, 4695-4704. - cotransporter KCC2 in setting the Cl gradient for hyperpolarizing [4] Jarolimek, W., et al. (1998) J. Neurosci. 18, 4001-4007. inhibition and (3) on presynaptic modulation of GABA release by [5] Radnikow, G. and Misgeld, U. (1998) J. Neurosci. 18, 2009-2016. retrograde signaling. Structure of the group - GABA receptor mediated postsynaptic inhibition and Cl Group leader Ulrich Misgeld transport Postdoctoral fellows Xiuxin Liu, Stefan Titz, A functional assay for KCC2 revealed that KCC2 maintains a con- Yevgenij Yanovsky, Wei Zhang stant intracellular Cl- concentration which is set by the extracellular Graduate students Wolfgang Kelsch, Sandra Mades K+ concentration. Development of transport activity in cultured Technicians Cornelia Heuser, Andrea Lewen hippocampal neurons involves a tyrosine kinase dependent post- translational modification which is promoted by the stimulation of Contact IGF-1 receptors. Blockade of KCC2 by the loop diuretic furosemide Prof. Dr. Ulrich Misgeld requires an allosteric modulation by monovalent cations. During Institut für Physiologie und Pathophysiologie + Universität Heidelberg hepatic encephalopathia, KCC2 is the pathway across which NH4 Im Neuenheimer Feld 326 enters neurons thereby disrupting their function. 69120 Heidelberg, Germany A +49-(0) 6221 - 54 4560/4558 E +49-(0) 6221 - 54 4038 Retrograde dopaminergic modulation of postsynaptic K [email protected] inhibition in substantia nigra http:// www.rzuser.uni-heidelberg.de/~bn2/misgeld/arbgr_mi.html Dopaminergic cells release dopamine from their somata and dendrites. Dopamine D1 receptors on striatonigral GABAergic termi- 61 Stefan Offermanns

Cellular signaling onstrate that plexin-B family members associate through their C-termini with Rho guanine- Stefan Offermanns nucleotide-exchange-factors MD 1991 Free University of Berlin, Germany PDZ-RhoGEF and LARG. PDZ- RhoGEF/LARG mediate Sema4D/ Postdoctoral work at California Institute of Technology and Free plexin-B1-induced RhoA activa- University of Berlin tion, and a dominant-negative Heisenberg fellow 1999-2000 form of PDZ-RhoGEF blocks Professor of Pharmacology and Toxicology, Heidelberg, since 2000 Sema4D-induced growth cone collapse in neurons. This indi- Current Research, Future Projects and Goals cates that the interaction of mam- The central theme of our research are the functions of various malian plexin-B family members GTPases in cellular signaling pathways. We are especially dealing with the multi-domain-proteins with heterotrimeric G-proteins which are regulated by G-protein- PDZ-RhoGEF and LARG represents an essential molecular link coupled receptors (GPCRs) as well as with monomeric GTPases of between plexin-B and localized, RhoA-mediated downstream sig- the Rho-family (Rho, Rac, Cdc42). In addition to projects dealing naling events, which underly various plexin-mediated cellular phe- with orphan GPCRs and the function of Gq/G11-, G12/G13- and nomena including axonal growth cone collapse. Rho-family members in platelets, immune cells and the in the cardiovascular system we have a particular interest in the role these Selected Publications signaling processes play in the modulation of neuronal functions as [1] Klages, B. et al. (1999) J. Cell Biol. 144:745-754 well as in neural morphogenesis. [2] Wettschureck, N. et al. (2001) Nat. Med. 7, 1236-1240 [3] Kleppisch, T., et al. (2001) J. Neurosci. 21, 4943-4948 The role of Gq/11-and G12/13-mediated signaling pathways in [4] Swiercz, J., et al. (2002) Neuron 35, 51-63 the function and development of the CNS [5] Tunaru, S. et al. (2003) Nat. Med. 9 (in press) There is increasing evidence that in particular GPCRs coupling to the ubiquitously expressed G-proteins of the Gq/G11- and G12/ Structure of the group G13-families are involved in various aspects of nervous system Group leader Stefan Offermanns function. While Gq/G11 mediate the activation of ß-isoforms of Postdoctoral fellows Robert Grosse, Jukka Kero, phospholipase C, G12/G13 lead to the activation of the small Barbara Leutgeb, Stephan Vogt, GTPase RhoA. Both pathways are involved in cell migration, axonal Nina Wettschureck, Alexandra Zywietz pathfinding as well as neuronal cell differentiation in vitro. To study Graduate students Dagmara Dettlaff, Arul Sakkaravarthi, Jakub the role of Gq/11- and G12/13-mediated signaling processes dur- Swiercz, Sorin Tunaru ing the development of the intact nervous system, we plan to gen- Technicians Karin Meyer, Anke Rippberger, Anke erate and analyze mouse lines which lack G q/G 11 and G 12/G 13 Rogatzki, Barbara Wallenwein in defined compartments of the developing nervous system using Cre/loxP-mediated recombination. Contact Prof. Dr. Stefan Offermanns Functions and signaling mechanisms of plexin-B family members Pharmakologisches Institut Mammalian plexins are widely-expressed transmembrane proteins Universität Heidelberg which mediate the effects of transmembraneous and secreted mem- Im Neuenheimer Feld 366 bers of the semaphorin family in various tissues. In neuronal cells, 69120 Heidelberg they are mainly involved in the repulsive activities of semaphorins. Germany Recently, plexins have been linked to the regulation of small A +49-(0) 6221 - 54 8246/7 GTPases of the Rho family. Activation of plexin-B1 by semaphorin E +49-(0) 6221 - 54 8549 K 4D (Sema4D) enhances binding of GTP-bound Rac1 to plexin B1 [email protected] and has been suggested to induce RhoA activation. We could dem- http://www.pharmakologie.uni-hd.de 62 G. Elisabeth Pollerberg Growth and orientation of axons during development of the vertebrate nervous system

G. Elisabeth Pollerberg

PhD (Dr. rer. nat.) 1986, Department of Neurobiology, University of Heidelberg Postdoctoral work (1986-87), European Molecular Biology Laboratories (EMBL), Heidelberg Group leader (1988-1996, Max-Planck-Institute for Developmental Biology, Tübingen Professor (1996-98), Department of Developmental Biology, Institute of Zoology, Giessen Selected Publications Professor (since 1999), Department of Developmental Neurobiology, [1] Stoeckli, E. T et al. (1997) Neuron, 18: 209 Institute of Zoology, Heidelberg [2] Mack, T. G. A et al. (2000) Mol. Cell. Neurosci., 15, 51-65 [3] Faivre-Sarrailh, C. F. (2000) J. Cell Sci., 112, 3015-3027 Current Research [4] Yamagata, M. (2000) Dev. Growth Diff., 41, 575-587 We are interested the cellular and molecular processes underlying the “wiring” of the vertebrate central nervous system. In particular, we study interactions of elongating axons (and the growth cones at Structure of the group their tips) with their environment and the transformation of such Group leader G. Elisabeth Pollerberg interactions into directed growth. Postdoctoral fellows Heike Kleinholz, Karsten Thelen Using the chick embryo visual system as a model, we investigate the Graduate students Michael Köster, Hasan Avci, Christian Hahn, functions of cell adhesion molecules (CAMs) for growth and orien- Pavol Zelina, Bettina Mayer tation of retinal ganglion cell axons. We are also investigating the Technicians Monika Zieher-Lorenz, Susanne Bergmann role of cytoskeletal components and intracellular signalling molecules in the growth cone. We study these proteins for example in growth cones challenged with substrate borders in vitro or in axons Contact growing in the retina, manipulated in their expression of the proteins of interest. Prof. Dr. G. Elisabeth Pollerberg Institut für Zoologie, Abt. Entwicklungsneurobiologie Universität Heidelberg Future Projects and Goals Im Neuenheimer Feld 232 CAMs, cytoskeletal components, and intracellular signalling mole- D-69120 Heidelberg cules will be investigated for their role in axonal orientation, aiming Germany at the detection of the entire signalling process from the growth A +49-(0) 6221 - 54 6370 E cone membrane to cytoskeleton. For this, we will employ cell bio- +49-(0) 6221 - 54 637 K logical, biochemical and molecular biological approaches. Studies [email protected] http://www.zoo.uni-heidelberg.de/gep will be also performed in the intact embryo (in ovo transfections, GFP life imaging) to gain insight in the complex interplay on systemic level.

63 Klaus Sartor

Focal cerebral ischemia, functional MR- Further projects: tomography • Advanced MR imaging of white matter and intracerebral hemorrhage Klaus Sartor • MR spectroscopy and MD 1966, University of Düsseldorf diffusion MR imaging in brain Postdoctoral work at Mercy Hospital & Medical Center, Chicago (USA), disorders of early childhood AK Altona, Hamburg, and UCSF (USA) • MR diffusion tensor imaging 1983 - 1989 Associate Professor at Mallinckrodt Institute of Radiology, in brain tumors Washington University School of Medicine, St. Louis (USA) • Intraoperative MR imaging , Head, Division of Neuroradiology, University of Heidelberg Medical CT angiography and Center, since 1989 perfusion CT Future Projects and Goals Current Research Our major goal is to use quantitative and functional imaging tech- Imaging of Early Stroke niques to better diagnose and understand diseases at a very early The Division of Neuroradiology is involved in a multitude of stage and to test and monitor treatment strategies. With a combi- research areas, most of which are interdisciplinary in nature. A nation of diffusion tensor imaging, magnetic resonance spectros- major research focus is ischemia. From 1993 to 1999, as part of a copy and quantitative perfusion imaging we aim to characterize DFG research group pathophysiological studies and studies of new tissue types in vivo as to their microanatomy, blood supply and therapeutic strategies for stroke were conducted. Neuroradiology metabolism. contributed by establishing new MRI techniques with which focal cerebral ischemia can be detected only minutes after the onset of Selected Publications symptoms and with which the success of therapy can be monitored. [1] Heiland S, et al. (1998) Magn Reson Imaging 17, 21-27 Stroke research is continued as part of a large multicenter project [2] Jansen O, et al. (1999) Lancet 353; 2036-2037 (http://www.kompetenznetz-schlaganfall.de/). The newly devel- [3] Stippich C, et al. (2000) Neurosci Lett 285, 155-159 oped acute stroke protocol includes T2-weighted MRI, diffusion [4] Dietrich O, et al. (2001) Magn Reson Med 45, 448-453 MRI, perfusion MRI, and MR angiography. [5] Fiebach JB, et al. (2002) Stroke 33, 2206-2210

Functional Magnetic Resonance Imaging Structure of the group Another area of research is functional MR imaging. Now that the Group leader Klaus Sartor initial methodology-oriented studies have been concluded, this Scientific staff Jochen Fiebach, Stefan Hähnel, Inga Harting, technique is employed for the planning of brain tumor surgery as Marius Hartmann, Sabine Heiland,Klaus Kirchhof, well as in pain research. Bodo Kress, Peter Schramm,Christoph Stippich, Thomas Wilhelm Functional and Quantitative Techniques in MR Imaging Graduate students Jens Georgi, Gregor Jost, Holger Schmitt In the group of Sabine Heiland, several MR techniques have been Technicians Petra Freudenmacher, Martin Kohl developed to study microanatomy, microvasculature and metabolism of brain in vivo. One of these new techniques is an MR method Contact to simultaneously measure cerebrovascular parameters and the per- Prof. Dr. Klaus Sartor meability of blood-brain-barrier. Another method based on diffu- Abt. Neuroradiologie, Universitätsklinikum Heidelberg sion-weighted MRI allows to measure the cell size as well as the Im Neuenheimer Feld 400 permeability of the cell membranes. We also attempt to quantify 69120 Heidelberg, Germany the concentration of different metabolites by proton MR spectros- A +49-(0) 6221 - 56 7566, E +49-(0) 6221 - 56 4673 copy and the concentration of macromolecules (e.g. myelin) by a K [email protected] quantitative, volumetric method of magnetization transfer imaging. http://www.med.uni-heidelberg.de/neuro/neurorad/en/home.shtml 64 Johannes Schröder Functional neuroimaging correlates of neural plasticity in age-associated neurocognitive disorders

Johannes Schröder

MD 1984 University of Bochum, Germany Postdoctoral work at the Universities of Bochum and Heidelberg; Research Fellow UC Irvine 1992 Professor of clinical Psychiatry, Section of Geriatric Psychiatry, Heidelberg, since 2000

Current Research Selected Publications The cerebral changes underlying psychiatric disorders can be reli- Schröder J., et al., (2001) Biol Psychiatry 49(5), 426-436. ably identified using structural and functional neuroimaging tech- Karlsson H. et al., (2001) PNAS 98(8):4634-4639. niques, in particular magnetic resonance imaging. Previous research Schönknecht P. (in press) Neurosci Lett has investigated cerebral changes in schizophrenia and Alzheimer´s Hempel A. et al., (in press) Schiz Res disease with respect to psychopathological symptoms, cognitive Pantel J. et al., (in press) Am J Psychiatry deficits, and potential molecular markers. Recent studies focus on the functional mechanisms of basic processes involved in these disorders. This approach may be illustrated by a recent study of corti- Structure of the group cal activation under a working memory task during training which Group leader Johannes Schröder revealed a reduced activation – suggesting greater efficacy – of Scientific staff Marco Essig, Johannes Pantel, cerebral activation in the controls but a reallocation of former Graduate students Albrecht Hempel, Peter Schönknecht hypofrontal activation patterns in patients with schizophrenia. Sonja Barth, Christina Bottmer, Anne Future Projects and Goals Eschen, Aoife Hunt, Philipp Thomann Further studies are designed to address the following questions: Contact

• Are consistent activation changes observed during training of Prof. Dr. Johannes Schröder declarative and procedural memory functioning? Sektion Gerontopsychiatrie Universität Heidelberg • Do these mechanisms adapt to physiological aging and age- Voßstr. 4 related conditions such as mild cognitive impairment or 69115 Heidelberg Alzheimer´s disease? Germany A +49-(0) 6221 - 56 4403 • Which neurobiological factors, such as the Catechol-O- E Methyltransferase polymorphism, APP metabolism, have +49-(0) 6221 - 56 5327 K [email protected] modulatory effects?

65 Markus Schwaninger Molecular stroke research

Markus Schwaninger

1987 doctoral thesis in pharmacology, University of Freiburg Training in Neurology (FU Berlin, Heidelberg) Postdoctoral work in Molecular Pharmacology (Göttingen) Now group leader "molecular stroke research"

Current Research Stroke is the leading cause of disability in adults, but therapy is still limited. Important mechanisms in the molecular pathophysiology of stroke are an inflammatory response in the ischemic brain and apo- Selected Publications ptosis of neurons. In the investigation of these two key players we focus on the role of gene expression. Starting point is the charac- [1] Schwaninger M, Sallmann S, Petersen N, Schneider A, Prinz S, terization of gene expression in cerebral ischemia by microarray Libermann TA, Spranger M (1999) J. Neurochem. 73, 1461-1466. techniques. We then analyse the role of a selected number of indi- [2] Schneider A, Martin-Villalba A, Weih F, Vogel J, Wirth T, Schwaninger M vidual genes, that are induced by cerebral ischemia and are alleged (1999) Nat. Med. 5, 554-559. players in the inflammatory response. For this purpose we use [3] Sallmann S, Jüttler E, Prinz S, Petersen N, Knopf U, Weiser T, transgenic techniques and a mouse model of cerebral ischemia. Schwaninger M (2000) J. Neurosci. 20, 8637-8642. One focus of the group is the transcription factor NF-xB. In order [4] Schwaninger M, Petersen N, Prinz S, Sallmann S, Neher M, Spranger M to block activation in a cell type specific manner in the CNS we (2000) Glia 31, 51-58. have generated mice that express the dominant NF-xB-inhibitor [5] Herrmann O, Tarabin V, Suzuki S, Attigah N, Coserea I, Schneider A, nmlxB in astroglial cells and neurons. In addition, we are studying Vogel J, Prinz S, Schwab S, Monyer H, Brombacher F, Schwaninger M transgenic mice, in collaborations with other groups, that lack com- (2003) J. Cereb. Blood Flow Metab., in press. ponents of the NF-xB signaling cascade. These studies will help to elucidate the significance of NF-xB as a central regulator of inflam- Structure of the group mation and apoptosis in the CNS. Group leader Markus Schwaninger Postdoctoral fellows Oliver Herrmann, Eric Jüttler Future Projects and Goals Graduate students Dana Acalovschi, Ioana Potrovita, Victoria To unravel the regulatory networks underlying gene induction in Ta ra bi n , We n Z h a n g cerebral ischemia we will use in silico-analysis of promoters of Technician Anja Buhl induced genes and in vivo-experiments with mice deficient of selective transcription factors. The identified functional pathways will be Contact tested for their clinical significance by polymorphism studies in stroke patients. Priv.-Doz. Dr. med. Markus Schwaninger Neurologische Klinik Universität Heidelberg Im Neuenheimer Feld 400 69120 Heidelberg Germany A +49-(0) 6221 - 56-7504 E +49-(0) 6221 - 56-5461 K [email protected] http://www. krz.uni-heidelberg.de/neuro/n/welcome_j.html

66 Peter H. Seeburg

The role of glutamate receptor subtypes in Gene expression in, and pulsatile activity of, hypothalamic gona- short- and long-term memory dotrophin releasing hormone (GnRH) producing neurons in Peter H. Seeburg transgenic mice expressing GFP in these cells. Origin and mechanism PhD in Genetics 1975 University of Tuebingen of the pulse generator for the 1975 - 1977 Po s t d o c to ra l wo r k a t U C S F pulsatile activity of this small Adjunct Assist. Professor in Medicine at UCSF, Senior and Staff (800 in the rodent) and scat- Scientist at Genentech, Inc., South San Franciso, 1977-1987 tered population of neurosecre- Full Professor, University of Heidelberg, 1987-1995, tory cells are unknown and Director at the Max-Planck-Institute for Medical Research Heidelberg, constitute the focus of this since 1996 project. Future Projects and Goals Current Research Investigate link between synaptic plasticity and different forms of Generation of mouse mutants via gene manipulation in embryonic memory stem cells for the regulated expression of sequence-altered subunits for ionotropic glutamate receptors of the AMPA, NMDA and Selected Publications kainate subtypes. Sequence changes comprise functional ablation, green fluorescent protein (GFP)-fusion, mutations in the inner [1] Sprengel, R., et al. (1998) Cell 92, 279-289. channel lining, mutations affecting gating kinetics and desensitiza- [2] Feldmeyer, D., et al. (1999) Nature Neuroscience 2, 57-64. tion, C-terminal alterations affecting trafficking to synapses and [3] Zamanillo, D., et al. (1999) Science 284, 1805-1811. interaction with components of intracellular signaling cascades. [4] Mack, V., et al. (2001) Science 292, 2501-2504. Expression regulation is attempted by the use of newly engineered [5] Reisel, D., et al. (2002) Nature Neuroscience 9, 868-873. versions of the ‘Cre-lox’ system and of tetracycline-mediated transcriptional activation/repression. Aims are to study molecular Structure of the group mechanisms at the postsynaptic side underlying fast excitatory Group leader Peter Seeburg synaptic transmission and activity-modulated synaptic strength. Staff Miyoko Higuchi, Georg Köhr, Pavel Osten, Rolf Sprengel Studies of the physiological relevance of RNA editing by adenosine Postdoctoral fellows Rachel Aronoff, Thilo Borchardt, Jochen Hartner, deamination.These studies include the conditional ablation in mice Heinz Krestel, Martin Schwarz, Frank Single, of the three known mammalian RNA dependent adenosine deami- Daniel Spergel nases, ADAR1-3, which are currently the only candidate enzymes Graduate students Thorsten Bus, Tanjew Dittgen, Simone Freese,Boris Hambsch, Alexander Kolleker, Liliane Layer, Pawel for RNA editing by adenosine deamination. ADAR2 edits in vitro Licznerski, Verena Pawlak, Pradeep Punnakal, Bettina the Q/R site of GluR-B pre-mRNA and thus ensures the low perme- Schupp, Quan-Xiang Wei, Francesca Zammaretti, ability to calcium of hetero-oligomeric AMPA receptor channels Technicians Carmen Großkurth, Horst Großkurth, Sabine configured with this edited subunit. Interference with Q/R site Grünewald, Annette Herold, Juliana Kern, Judith editing of GluR-B, either by an appropriate sequence change in the Müller GluR-B gene or by ADAR2 ablation leads in the mouse to a prema- turely lethal, seizure-prone phenotype. No obvious phenotypical Contact consequences arise from ADAR2 ablation if within the GluR-B gene Prof. Dr. Peter Seeburg the ‘edited’ codon is exchanged for the unedited one. This demon- Max-Planck-Institut für medizinische Forschung, Molekulare Neurobiologie strates that of all the possible sites edited by ADAR2 (the enzyme Jahnstraße 29 is found in many tissues), the Q/R site in the GluR-B transcript is 69120 Heidelberg, Germany physiologically the most important one. A +49-(0) 6221 – 486 495, E +49-(0) 6221 – 486 110 K [email protected] http://www.mpimf-heidelberg.mpg.de/ 67 Jeremy C. Smith Computer simulation of ion pumps

Jeremy C. Smith

PhD London University 1985 Postdoc Harvard University Chemistry Department 1985-1989 Group Leader Biology Dept., CEA Saclay 1989-1998 Professor (C4) Biology and Physics Departments Heidelberg University. 1998 -

Current Research Structure of the group Molecular dynamics simulations are performed of proteins and Group leader Jeremy C. Smith peptides. Of particular relevance to neuroscience are the investiga- Stefan Fischer (C1) tions on ion pumps which we are now undertaking in the context of Emmy-Noether fellow G. Matthias Ullmann and his group a DFG ‘Forschergruppe’ consortium aimed at obtaining a theoreti- Andrei Borodich, Raghu Nath cal understanding of retinal proteins, together with research aimed Behera, Nicolas Calimet, Edda at understanding membrane fluidity and control and modelling of Kloppmann the serotonin binding site of 5HT2B receptors.

Future Projects and Goals Graduate students Jessica Agarwal, Torsten Becker, Zoe Cournia, Andreea Gruia, Sampath Koppole, Understanding of the functioning of membranes and membrane Lars Meinhold, Frank Noe, Durba Sengupta, proteins at atomic detail. Sonja Schwarzl, Ileana Tecuatl, Alexander Selected Publications Tournier, Andrea Vaiana, Sidonia Zafiu. Technician Bogdan Costescu [1] Topham, C.M., and Smith, J.C. (1999). Journal of Molecular Biology 292, 5, 1017-1038. [2] Reat, V., et al. (2000) Proceedings of the National Academy of Contact Sciences (U.S.A.) 97, 18, 9961-9966. Prof. Dr. Jeremy C. Smith [3] Manivet, P., et al. (2002) Journal of Biological Chemistry 277(19), Interdisziplinäres Zentrum für Wissenschaftliches Rechnen (IWR) 17170 - 8 . Computational Molecular Biophysics Universität Heidelberg [4] Huynh, T., et al. (2002) Biophysical Journal 83, 681-698. Im Neuenheimer Feld 368 [5] Merzel, F., and Smith, J.C. (2002) Proceedings of the National 69120 Heidelberg Academy of Sciences (U.S.A) 99(8), 5378-5383. Germany A +49-(0) 6221 - 54 8857 E +49-(0) 6221 - 54 8868 K [email protected] http://www.iwr.uni-heidelberg.de/

68 Rainer Spanagel

The neurobiology of drug dependence • Identification of depression relevant gene transcripts in a rat model of learned Rainer Spanagel helplessness PhD 1991 M P I o f N e u r o b iology, Martinsried Postdoctoral work at MPI of Psychiatry, Munich 1991-1995 Group leader at MPI of Psychiatry, Munich 1996-1999 Professor of Psychopharmacology at the Central Institute of Mental Health (CIMH) 2000 Head of the center for basic research at the CIMH 2001

Current Research Selected Publications We are using a newly established model to generate alcohol-dependent rats or mice. Behavioral, pharmacological and neurochemical [1] Timpel P, Spanagel R, Sillaber I, Kresse A, Reul JMHM, Stalla J, examinations on alcohol-dependent rodents will help us to under- Planquet V, Steckler T Holsboer F, Wurst W (1999) Nature Genetics stand the neurobiological mechanisms of addictive behavior. Stud- 19 , 162-166. ies with mutant mice will help us to identify genes involved in the [2] Spanagel R, Weiss F. (1999) Trends Neurosci. 22, 521-527. initiation of drug-seeking behavior. In addition, an organ bank with [3] Sillaber I, Rammes G, Zimmermann S, Mahal B, Zieglgänsberger W, different alcohol-preferring rat lines (AA, P, HAD) has been estab- Wurst W, Holsboer F, Spanagel R. (2002) Science 296, 931-933. lished. The aim of the organ bank is the characterization of molecu- [4] Abarca C, Albrecht U, Spanagel R. (2002) Proc. Natl. Acad. Sci. USA larbiological cascades (with DNA chip technology) involved in 99, 9026-9030. alcohol-derived diseases. In a comparative approach the effects of [5] Spanagel R,. Sigmund SV, Cowen M, Schroff KC, Schumann G, Fiserova opioids and psychostimulants are studied. Our close collaboration M, Sillaber I, Wellek S, Singer MV, Putzke J. (2002) J. Neurosci. 22, with the Clinic of Addictive Behavior at the CIMH (Prof. K. Mann) 8676-8683. enables us to rapidly validate our preclinical findings in human addicts. Here the primary goal is the development of new anti- Structure of the group relapse compounds and especially the development of an individu- Group leader Rainer Spanagel ally adapted pharmacotherapy. Therefore, alcohol-dependent ani- Postdoctoral fellows Peter Gebicke-Haerter, Daniel Bachteler mals will be separated into different behavioral and neurobiological Michael Cowen, Sören Siegmund, Karl phenotypes which will then be treated with a corresponding anti- Schroff, Armani Yousef, Carles Sanchis relapse compound. Reinstatement of alcohol-seeking behavior Graduate students Carolina Abarca, Valentina Vengeliene, induced by different stimuli will be measured subsequently. Ta rek Zoghul, Fernado Essman Future Projects and Goals Technicians Sabrina Koch, Claudia Schäfer, Brandon Cline • Idendification and validation of molecular targets for pharmacological treatment of alcohol dependence Contact • Individual adapted pharmacotherapy Prof. Dr. Rainer Spanagel • Development of alcohol-induced organic diseases in rats Department of Psychopharmacology • Interaction of per genes with drug dependence Central Institute of Mental Health University of Heidelberg • Neurochemical and molecular changes during chronic drug J5 exposure and chronic pain 68159 Mannheim • The role of glucocorticoid receptors in acute and chronic A +49-(0)621-1703833, E +49-(0)621 -1703837 effects of alcohol and cocaine K [email protected]

69 Brigitte Wildemann

Peripheral immune tolerance and Multiple undefined. Current experiments complement clinical and basic Sclerosis molecular and immunologic studies to investigate the possibiltiy Brigitte Wildemann that a deficiency in the generation, effector function and/or 1983 D r. m e d . + + survival of CD4 CD25 Treg cells 1984 - 1990 Resident in Neurology and Psychiatry, Univ. of Heidelberg is involved in the breakdown of 1986 Research Fellow, Dept. Immunology, Hammersmith Hospital, immune-tolerance in MS patients. London The study includes the isolation 1990 Licence as neurologist and characterization of Treg cells 1993 Habilitation in treatment naive patients with 1994/1995 Research Fellow, Dept. Neurology and Neuroscience, Johns relapsing remitting MS and Hopkins University, Baltimore healthy persons (Collaboration 2000 Professor of Neurology Peter H. Krammer, DKFZ Heidelberg). 2001 Head of section „Molecular Neuroimmunology“, Department of Neurology, University of Heidelberg Future Projects and Goals We will assess the implication of Treg cells in tumor immunity asso- Current Research ciated with paraneoplastic neurologic disorders as well as the Our present research intends to advance our understanding on the spread of hematologic malignancies and solid tumors to the central nervous system. role of immunoregulatory T cells (Treg) in mediating the breakdown of immune-tolerance in multiple sclerosis (MS). Rationale Multiple Selected Publications sclerosis (MS) is an autoimmune and predominantly T cell mediated demyelinating disease of the central nervous system (CNS). A Wildemann, B., et al. (1996) Science 274: 1917-1921 prerequisite for the induction of autoimmunity within the CNS is Wildemann, B., et al. (1997) Neurology 48: 1341-1346 the activation and extravasation of circulating self-reactive T lym- Wildemann, B. et al. (1998) Neurology 50: 693-697 phocytes with specificity for myelin components. Since myelin-spe- Storch-Hagenlocher, B. et al. (2000) Ann Neurol 47: 211-217 cific autoreactive T lymphocytes are uniformly present in the Wildemann, B., et al. (2001) J Neurol 248: 127-130 peripheral T cell repertoire in both patients with MS and healthy persons a dysfunction or failure of peripheral immune-tolerance Structure of the group mechanisms may be critically involved in the emergence of autoim- Group leader Brigitte Wildemann munity within the CNS. In concordance with this assumption we Postdoctoral fellows Juergen Haas, Andreas Hug, Andrea have recently demonstrated that peripheral T cell homeostasis is Viehoever significantly impaired in patients with relapsing remitting MS as a Graduate students Mirjam Korporal, Isabella Schroeder, Andrea result of an age-inappropriately declined thymic export of T lym- Filser phocytes. In experimental animal models the maintenance of Technician Brigitte Fritz immune-tolerance towards self-antigens correlates with the thymic dependent generation of a specific T cell subset that harbor an Contact autoimmune preventive capacity and „actively“ downregulate the Prof. Dr. Brigitte Wildemann activation and proliferation of self-reactive T lymphocytes. These Section of Molecular Neuroimmunology professional immunoregulatory T lymphocytes reside in the Department of Neurology reg University of Heidelberg + CD4 subset of thymocytes and peripheral T cells, constitutively Im Neuenheimer Feld 400 coexpress CD25 and comprise 2-5% of the CD4+ T cell compart- 69120 Heidelberg, Germany A +49-(0) 6221 - 56 7504, E +49-(0) 6221 - 56 5461 ment. Although CD4+CD25+ T cells are also present in humans reg K [email protected] their relevance for the development of autoimmune disease is still

70 Joachim Wittbrodt

Vertebrate retina development and Future Projects and Goals differentiation We will take molecular, genetic and cell biological approaches to: - generate and identify novel Joachim Wittbrodt early brain and eye mutants following novel mutagenesis strate- PhD 1991 University of Munich, Germany gies developed in the lab; Postdoctoral training at the Biocenter, University of Basel, Switzerland - investigate the genetic and Junior Group Leader at the Max Planck Institute for Biophysical molecular interactions leading to Chemistry, Göttingen, Germany the establishment and patterning At EMBL since 1999 of the forebrain and the early eye field; Current Research - identify genes by subtractive In a continuation of neural induction and in parallel with early pat- approaches involving mutants terning events in the forebrain, the optic vesicle forms as a lateral lacking eyes as well as medaka ES-cells transfected with candidate protrusion of the forebrain. The vertebrate eye is composed of genes; neuro-ectodermal (optic cup) and surface ectodermal (lens, cor- - study gene function and interaction of known and novel "eye nea) derivatives and it emerges from an epithelial anlage by induc- genes" using novel antisense strategies. tive interactions beginning as early as the late stages of It is our goal to understand the molecular and cellular interactions gastrulation. While the formation of the optic vesicle can be con- that lead to the patterning of the early brain and to eye formation. sidered part of forebrain patterning, lens induction occurs through planar signals emanating from the anterior neural plate. These sig- Selected Publications nals induce lens formation in the competent tissue of the lens pla- [1] Carl, M., et al. (2002) Development, 129, 4057-4063. code. Most of our current knowledge of eye development is based [2] Wittbrodt, J., et al. (2002) Nature Reviews Genetics, 3, 53-64. on classical embryological experiments. Because of their transpar- [3] Loosli, F., et al. (2001) Development 128, 4035-4044. ency, rapid early development and short generation time, fish [4] Arendt, D., et al. (2001). Nature, 409, 81-85. (medaka/zebrafish) are well suited for detailed study of this pro- [5] Winkler, S. , et al. (2000) Development, 127, 1911-1919. cess. Structure of the group We investigate medaka eye development following three comple- Group leader Joachim Wittbrodt mentary experimental strategies. Postdoctoral fellows Felix Loosli, Juan-Ramon Martinez-Morales, (1) The isolation and collection of genes expressed in spatially Rebecca Quiring and/or temporally restricted patterns in the developing brain, with emphasis on transcription factors and signaling cascades involving Graduate students Flippo DelBene, Clemens Grabher, Caroline TGF-ß-like genes and FGF-receptor gene families as well as on Iquel, Martina Rembold genes that are expressed in response to Six3 and Pax6 activity. In Technicians Erika Grzebisz, Annette Krone, Beate addition, novel eye genes have been identified based on their Wittbrodt expression patterns. (2) Functional analyses involving gain-of-function studies by Contact ectopically expressing transgenes in the developing eye. Jochen Wittbrodt, PhD (3) Functional studies involving a mutagenesis screen and mutant EMBL, Developmental Biology Programme analysis. In a collaborative screen of more than 1200 genomes, Meyerhofstrasse 1, Postfach 10.2209 more than 100 mutants with eye phenotypes were identified, three D-69012 Heidelberg, GERMANY of which completely lack eyes. We identified the mutation causing A +49 (0)6221 387 576, E +49 (0)6221 387 166 the eyeless phenotype in medaka by positional cloning and rescue K [email protected] analysis. http://www-db.embl-heidelberg.de:4321/emblGroups/g_66.html

Central Facilities

Teaching Central Facilities Central Facilities

Coordinator Neuroanatomy Dr. Otto Bräunling Ursel Lindenberger A +49 (0)6221/ 548694 A +49 (0)6221 / 548228 +49 (0)6221 / 5639007 E +49 (0)6221 / 545604 E +49 (0)6221 / 546700 K [email protected] K [email protected] i Institut für Anatomie und Zellbiologie i Neurobiologie der Universität Heidelberg Abt. Neuroanatomie, Im Neuenheimer Feld 364 Im Neuenheimer Feld 307 D-69120 Heidelberg 69120 Heidelberg Germany Germany

Central Secretary Clinical Neurobiology Dipl. Biol. Ute Volbehr Laura Winkel, Catherine Munzig A +49 (0)6221 / 548228 A +49 (0)6221 / 562401 E +49 (0)6221 / 545604 E +49 (0)6221 / 561397 K [email protected] K [email protected], i Institut für Anatomie und Zellbiologie [email protected], [email protected] Abt. Neuroanatomie, i Institut für Klinische Neurobiologie Im Neuenheimer Feld 307 der Neurologischen Klinik 69120 Heidelberg Im Neuenheimer Feld 364 Germany 69120 Heidelberg Germany Departmental Secretaries

Neurobiology Shipping of biologic materials Birgit Bell, Irmgard Büchler, Sean Leichtle Ruth Jelinek, INF 364, R122, Tel 548320 A +49 (0)6221 / 548219 E +49 (0)6221 / 546700 Cleaning kitchen and media preparation K [email protected] Ingrid Wartig, Heike Xoumpholpakdy, Oliver Teubner, [email protected] Detlef Spange (A 548617) i Neurobiologie der Universität Heidelberg Im Neuenheimer Feld 364 Central computing, photography and graphics unit 69120 Heidelberg Photography and computer service Germany Alan Summerfield A 545471, K [email protected]

Webmaster and computer service Sven Weimann A 548310, K [email protected]

74 Central Facilities

Central morphological Service Unit

Laserscanning microscopy, Calcium-Imaging, transmission Video-Microscopy electron microscopy, ultracryotomy, digital photography and Unit Place responsible: Funding image processing Microinjection- Neuro- Dr. H.-H. Gerdes SFB 317 A Transmission Electron Microscopy Videomicroscopy biology 548317 setup: Eppendorf Unit Place responsible: Funding Transjector, Leica Zeiss EM 10 Neuro- Andrea Hellwig Land Baden- microscope, biology A 545472 Württemberg Photometrix Zeiss EM 10 Neuro- Barbara Brühl Land Baden- Quantix2 digital anatomy A 548345 Württemberg camera Balzers MED010 Neuro- Andrea Hellwig Land Baden- Multi colour digital Neuro- Dr. H.-H. Gerdes SFB 488 Coating unit biology A 545472 Württemberg imaging setup: biology A 548317 Olympus/Till Ultracryotomy Photonics Unit Place responsible: Funding Analog imaging Neuro- Dr. H.-H. Gerdes SFB 488 setup: Hamamatsu biology A 548317 Leica Ultracut Neuro- Andrea Hellwig Land Baden- (SIT) camera A with FC-S biology 545472 Württemberg system Leica Ultracut Neuro- Prof. Dr. K. Gorgas SFB 488 Digital workstation Neuro- Dr. A. Schober Land Baden- A with FC-S anatomy 548664 I: Microscope: anatomy A 548229 Württemberg 548668 Zeiss Axioplan; / SFB 488 Camera: Zeiss Freeze Substitution Axiocam, Software: Unit Place responsible: Funding Zeiss Axiovision Leica EM AFS Neuro- Andrea Hellwig SFB 317 Digital workstation Neuro- Dr. A. Schober Land Baden- biology A 545472 II: Microscope: anatomy A 548229 Württemberg Zeiss Axiophot; Confocal Laserscanning Microscopy Camera: Olympus DP-10, Software: Unit Place responsible: Funding Soft Imaging/ Leica TCS 4D Neuro- Anja Eder SFB 317 Analysis 3.0 biology A 548355 Leica TCS SP2 Neuro- Anja Eder SFB 488 Cell Culture A biology 548355 Unit Place responsible: Funding Cell Culture Neuro- Jutta Fey SFB 488 Phosphoimager anatomy A 548399 FOR 302 Unit Place responsible: Funding Fuji Phospho- Neuro- Mark Bajohrs SFB 352 imager BAS biology A 548321 The IZN is using the animal house and transgene lab of the 1000 Zentralbereich Neuenheimer Feld, and the facility of Biomo- lecular Chemistry of the ZMBH for syntheses and structural analyses.

75 IZN Teaching Program

IZN Teaching Program • In situ Hybridisierung und Immunhistochemie im zentralen Nervensystem. H. Monyer, W. Wisden, S. Graduate College 791 Offermanns "Neural Development and Degenerative Processes: • Elektrophysiologische Ableitungen an Neuronen, die Basic Research and Clinical Implications" fluoreszierende Glutamatrezeptoren tragen. P. Seeburg • Simultane optische und elektrophysiologische Messungen synchroner Aktivität in einfachen Lectures for student members Netzwerken. U. Misgeld I. Entwicklung des Nervensystems. • Elektrophysiologische Messungen an neuronalen R. Friedrich, H. Hutter, C. Niehrs, E. Pollerberg, K. Unsicker, Schaltkreisen in akuten Hirnschnitten des Neocortex. V. Witzemann: D. Feldmeyer 1. Gene, Faktoren und Strukturen • Elektronenmikroskopie, neuronale Zellkultur. K. Unsicker 2. Neuronale Migration und axonales Pathfinding • Mikroinjektion von mRNA in Xenopus Oozyten. C. Niehrs 3. Synapsenbildung und Elimination 4. Krankheiten als Folge gestörter Entwicklung • Manipulation der neuromuskulären Synapse durch direkten Gentransfer in der Maus. V. Witzemann

II. Neurodegeneration: Zelluläre und systemische Aspekte. • In ovo Transfektion des Nervensystems beim K. Beyreuther, K. Fassbender, H.-H. Gerdes, T. Hartmann, Huhnembryo. E. Pollerberg M. Hennerici, H. Monyer, S. Offermanns, G. Schütz, • Langzeit-Schnittpräparate des Gehirns; Zwei-Photonen- M. Schwaninger: Mikroskopie in lebenden Präparaten. W. Denk 1. Akute Neurodegeneration 2. Chronische Neurodegeneration • Imaging neuronaler Aktivität im Zebrafisch. R. Friedrich • Analyse von Proteininteraktion mit Plasmon Resonanz. T. III. Erregende und hemmende Neurotransmission in dem sich Hartmann, K. Beyreuther entwickelnden Gehirn. • Herstellung und Analyse transgener C. elegans. D. Feldmeyer, W. Kuschinsky, U. Misgeld, W. Wisden H. Hutter

IV. Lernen und entwicklungsabhängige Plastizität. • Untersuchungsmethoden der Genexpression in neuralen D. Bartsch, W. Denk, F. Henn, H. Monyer, P. Seeburg: Zellen. M. Schwaninger 1. Somatosensorischer und visueller Cortex • Transgene Methoden in der Maus. G. Schütz, P. Seeburg 2. Plastizität im adulten Gehirn • Verhaltenstests in der Maus für Depression, Demenz und 3. Räumliches Lernen und der Hippocampus Sucht. F. Henn Methods courses • Neurologisches Kolloquium. K. Fassbender, M. Hennerici

• Dynamische Aspekte von sekretorischen Vesikeln: in vivo Analyse mit bildgebenden Verfahren. H.-H.Gerdes

• Zymogramme. W. Hacke

• Quantitative Autoradiographie zur Bestimmung von Funktionsgrössen im Gehirn. W. Kuschinsky

76 IZN Teaching Program

Lectures/Courses/Seminars summer term S Die Entwicklung des G.E. Pollerberg mit H. Hutter Nervensystems von und U. Ernsberger 2001 Modellorganismen: Systemische, zelluläre und molekulare Aspekte, 2st. S Einführung in die K.A. Nave Lectures Neurowissenschaft, 2st. S/Ü Verwendung von Software H. Simon, N.N. ZV Zellbiologie II: Molecular K. Unsicker, N.N. und Datenbasen in der Medicine, 2st. Molekularbiologie, 2st. ZV Zellbiologie IV: Molekulare K. Beyreuther, R. Brandt, FS IZN Seminar H. Bading, H. Monyer, und Zelluläre H.-H. Gerdes, K.A. Nave, Fortschritte in den K. Unsicker und die Neurobiologie, 2st. D. Langosch, B. Sakmann, Neurowissenschaften (für Gruppenleiter des IZN P. Seeburg, K.Unsicker Mitarbeiter des IZN und interessierte Studenten, in V Integrierte Neuroanatomie/ U. Misgeld, H. Monyer, englischer Sprache), 1st. Neurophysiologie, 3st. K. Unsicker V Neurobiology Lectures mit R. Brandt, D. Langosch und V Makroskopische und W. Kriz, K. Unsicker, S. Gastrednern (für die anderen Mikroskopische Anatomie, Mense, K. Tiedemann, K.H. Mitarbeiter des IZN und Forschungsgruppenleiter Entwicklungsgeschichte, Endlich, D. Hock interessierte Studenten, in des IZN und SFB 488 Neuroanatomie, 10st. englischer Sprache), 1st. (Begleitvorlesung zu den Kursen für Makroskopische, S SFB 488 Seminar K. Unsicker und Mikroskopische und ‘Molekulare und zelluläre Teilprojektleiter des SFB Neuroanatomie) Grundlagen neuraler 488 Entwicklungsprozesse’, 2st., V Neurologie/ W. Hacke, S. Kunze, ganzjähr. Neuroradiologie/ K. Sartor, H.-M. Meinck, Neurochirurgie H. Monyer und Mitarbeiter FS Mitarbeiterseminar: R. Brandt und Mitarbeiter Neuronales Zytoskelett (in Seminars, Courses, Colloquia englischer Sprache), 2st., ganzjähr. V/S Begleitseminar zum GP C R. Bischoff, U. Frank, FS Mitarbeiterseminar: H.-H. Gerdes und H.-H. Gerdes, M. Hassel, Sekretion von Mitarbeiter I. Hofmann, H. Hutter, Neuropeptiden (in F. M ö hrlen, H. Pöpperl, englischer Sprache), 2st. N. Rebscher, M. Schnölzer, FS Mitarbeiterseminar Protein- D. Langosch und Mitarbeiter D. Wiemann-Weiss Proteininteraktionen bei S Entwicklungsneurobiologie H. Simon, R. Brandt, Membranproteinen (in U. Ernsberger, , K. Unsicker englischer Sprache),1st., S Molekulare Zellbiologie: R. Brandt, H.-H. Gerdes, ganzjährig Seminar zu den Grundlagen D. Langosch, N.N. FS Journal Club for coworkers D. Langosch, W. Ruan der molekularen of the Department of Zellbiologie, 2st. Neurobiology and interested students, ganzjährig

77 IZN Teaching Program

S Mitarbeiterseminar: TGF- K. Unsicker und Mitarbeiter K Makroskopisch- D. Fahimi, W. Kriz, Betas (in englischer Anatomischer Kurs, K. Unsicker, S. Angermüller, Sprache), 2st. Abschnitte 4 und 5, K. Gorgas, S. Mense, J. Metz, S Journal Club für Mitarbeiter K. Unsicker und Mitarbeiter scheinpflichtig, 8st. K. Tiedemann, A. Völkl, der Neuroanatomie (in K.H. Endlich, R. Kinscherf, englischer Sprache), im N. Endlich, K. Huber, Wechsel mit D. Hock, H. Peterziel, Mitarbeiterseminar, 2st. J. Strelau, W.P. Trudrung, S Mitarbeiterseminar: H. Simon und Mitarbeiter N.N., N.N. Entwicklung der Mittelhirn K Kurs der Mikroskopischen D. Fahimi, W. Kriz, K. dopaminergen Neurone Anatomie, zweiter Teil, Unsicker, S, Angermüller, K. S Progress Report der H. Monyer, W. Wisden und scheinpflichtig, 4st. Gorgas, J. Kartenbeck, S. Arbeitsgruppe (in englischer Mitarbeiter Mense, J. Metz, K. Sprache), 2st. Tiedemann, A. Völkl, K.H. Endlich, U. Ernsberger, R. S Journal Club (in englischer H. Monyer, W. Wisden und Kinscherf, N. Endlich, D. Sprache), 1st.a Mitarbeiter Hock, C. Otto, H. Peterziel, S Forschergruppen-Seminar K. Unsicker und W.P. Trudrung, Tuckermann, ‘Zentrale aminerge Systeme Teilprojektleiter der J. Strelau, N.N., N.N. und Mechanismen’, 2st. Forschergruppe S Seminar “Anatomie”, 2st. D. Fahimi, W. Kriz, K. Unsicker, S. Angermüller, K. Gorgas, S. Mense, J. Metz, K. Tiedemann, A. Völkl, K.H. Endlich, R. Kinscherf, R. Witzgall, K. Zaar, D. Hock GP+, Grundpraktikum C4, R. Bischoff, U. Frank, K Physiologie, 5st. H.-H. Gerdes, M. Hassel, I. Hofmann, H. Hutter, F. Möhrlen, H. Pöpperl, N. Rebscher, M. Schnölzer, D. Wiemann-Weiss HP-B Praktikum: Moderne R. Brandt, T. Euler, Methoden in der H.-H. Gerdes, D. Langosch, Neurobiologie, 3wö., H. Monyer ganztäg., (HF, NF, Sachgruppe III) HP-C Forschungspraktikum R. Brandt, H.-H. Gerdes, Neurobiologie, 6wö., D. Langosch, A. Régnier- ganztäg., Vigouroux

78 IZN Teaching Program

Lectures/Courses/Seminars winter term S IZN Seminar H. Monyer, K. Unsicker und Fortschritte in den die Gruppenleiter des IZN 2001/02 Neurowissenschaften (für Mitarbeiter des IZN und interessierte Studenten, in englischer Sprache), 1st. Lectures S Neurobiology Lectures mit R. Brandt und die Gastrednern (für Mitarbeiter Gruppenleiter des IZN des IZN und interessierte V Biologie III, 5st. B. Dobberstein, H.-H. Gerdes, Studenten, in englischer Teil Zellbiologie vom D. Görlich, D. Robinson Sprache), 1st. 28.1.2002 – 15.2.2002 S Journal Club für Mitarbeiter Mitarbeiter der V Einführung zum N.N. der Neurobiologie (in Neurobiologie Hauptpraktikum A2, 1st. englischer Sprache), V Verwendung von Software H. Simon, R. Mosbach ganzjährig, 2st. und Datenbasen in der S Mitarbeiterseminar: R. Brandt und Mitarbeiter Molekularbiologie, 2st. Neuronales Zytoskelett (in V Neuroanatomie (im Rahmen K. Unsicker, S. Mense, J. Metz, englischer Sprache), der Vorlesung U. Ernsberger, R. Kinscherf, ganzjährig, 2st. Makroskopische und K. Huber, H. Peterziel, S Mitarbeiterseminar: Sekretion H.-H. Gerdes und Mitarbeiter Mikroskopische Anatomie), B. Reuss, J. Strelau von Neuropeptiden (in 10 st. englischer Sprache), 2st. V Entwicklungsbiologie/ Dozenten des Instituts für S Mitarbeiterseminar: TGF- K. Unsicker und Mitarbeiter Embryologie, 2st. Anatomie und Zellbiologie Betas (in englischer Sprache), 2st. V Integrierte Neuroanatomie S. Mense, H. Monyer, und –physiologie, 2st. U. Misgeld, Ch. Niehrs, S Journal Club für Mitarbeiter K. Unsicker und Mitarbeiter D. Rating, J. Sandkühler, der Neuroanatomie (in H. Seller, K. Unsicker, englischer Sprache), im M. Zimmermann Wechsel mit Mitarbeiterseminar, 2st. V Neurologie/Neuroradiologie/ W. Hacke, S, Kunze, K. Sartor, Neurochirurgie, 2st. H.-M. Meinck, H. Monyer und S Mitarbeiterseminar: H. Simon und Mitarbeiter Mitarbeiter Entwicklung der Mittelhirn dopaminergen Neurone Seminars, Courses, Colloquia S Progress Report der H. Monyer, W. Wisden und Arbeitsgruppe (in englischer Mitarbeiter S Einführung in die Zellbiologie H.-H. Gerdes, W. Wisden, Sprache), 2st. (für 1. Semester), 2st. S Journal Club (in englischer H. Monyer, W. Wisden und Sprache), 1st. Mitarbeiter S Molekulare Zellbiologie – H.-H. Gerdes, A. Régnier- Begleitseminar zur Vorlesung Vigouroux, W. Wisden S SFB 488 Seminar ‘Molekulare K. Unsicker und “Biologie III” und zelluläre Grundlagen Teilprojektleiter des SFB 488 neuraler Entwicklungs- prozesse’, 2st.

79 IZN Teaching Program

S Forschergruppen-Seminar K. Unsicker und ‘Zentrale aminerge Systeme Teilprojektleiter der und Mechanismen’, 2st. Forschergruppe S Ausgewählte Themen der Dozenten des Instituts für Zell- und Neurobiologie, 2st. Anatomie und Zellbiologie

K Neurobiologiekolloquium mit Forschungsgruppenleiter der Gastrednern (in englischer Neurobiologie Sprache), 1st. HP- Zellbiologie A2 N.N. A (Biochemie - Morphologie) 3-wöchig, ganztägig, (HF, NF, LA Sachgruppe III) HP- Laborpraktika: Moderne R. Brandt, H.-H. Gerdes, C Methoden in der Neurobiologie, 6-wöchig, ganztägig Kurs Neuroanatomie (im Rahmen K. Unsicker, S. Mense, J. Metz, des Makroskopisch- U. Ernsberger, R. Kinscherf, anatomischen Kurses), 8 st. K. Huber, H. Peterziel, B. Reuss, J. Strelau

80 IZN Teaching Program

Lectures/Courses/Seminars summer term S/Ü Verwendung von Software H. Simon, N.N. und Datenbasen in der 2002 Molekularbiologie, 2st. FS IZN Seminar H. Bading, H. Monyer, Fortschritte in den K. Unsicker und die Neurowissenschaften (für Gruppenleiter des IZN Lectures Mitarbeiter des IZN und interessierte Studenten, in englischer Sprache), 1st. ZV Zellbiologie II: Molecular K. Unsicker, N.N. Medicine, 2st. V Neurobiology Lectures mit U. Ernsberger, W. Wisden Gastrednern (für Mitarbeiter und die anderen ZV Zellbiologie IV: Molekulare H. Bading, K. Beyreuther, des IZN und interessierte Forschungsgruppenleiter und Zelluläre Neurobiologie, H.-H. Gerdes, K.A. Nave, Studenten, in englischer des IZN und SFB 488 2st. B. Sakmann, P. Seeburg, Sprache), 1st. K. Unsicker S SFB 488 Seminar K. Unsicker und V Integrierte Neuroanatomie/ U. Misgeld, H. Monyer, ‘Molekulare und zelluläre Teilprojektleiter des SFB Neurophysiologie, 3st. K. Unsicker Grundlagen neuraler 488 V Makroskopische und W. Kriz, K. Unsicker, Entwicklungsprozesse’, 2st., Mikroskopische Anatomie, S.Mense, K. Tiedemann, ganzjähr. Entwicklungsgeschichte, K.H. Endlich, D. Hock FS Mitarbeiterseminar: Gene H. Bading und Mitarbeiter Neuroanatomie, 10st. Regulation by Nuclear and (Begleitvorlesung zu den Cytoplasmic Calcium Signals Kursen für Makroskopische, in Neurons (in englischer Mikroskopische und Sprache), ganzjähr. Neuroanatomie) FS Mitarbeiterseminar: R. Brandt und Mitarbeiter V Neurologie/ W. Hacke, S. Kunze, Neuronales Zytoskelett (in Neuroradiologie/ K. Sartor, H.-M. Meinck, englischer Sprache), 2st., Neurochirurgie H. Monyer und Mitarbeiter ganzjähr. Seminars, Courses, Colloquia FS Mitarbeiterseminar: H.-H. Gerdes und Sekretion von Mitarbeiter V/S Begleitseminar zum GP C H.-H. Gerdes, U. Ernsberger, Neuropeptiden (in T. Euler, R. Friedrich englischer Sprache), 2st. HpS Entwicklungsneurobiologie H. Bading, H.-H. Gerdes, S Mitarbeiterseminar: TGF- K. Unsicker und Mitarbeiter U. Ernsberger, H. Simon, Betas (in englischer K. Unsicker Sprache), 2st. HpS Molecular Cell Biology H.-H. Gerdes, A. Cid, S Journal Club für Mitarbeiter K. Unsicker und Mitarbeiter Basics and new R. Kehlenbach, A. Régnier- der Neuroanatomie (in Developments, 2st. Vigouroux englischer Sprache), im Wechsel mit S Die Entwicklung des G.E. Pollerberg mit H. Hutter Mitarbeiterseminar, 2st. Nervensystems von und U. Ernsberger Modellorganismen: S Mitarbeiterseminar: H. Simon und Mitarbeiter Systemische, zelluläre und Entwicklung der Mittelhirn molekulare Aspekte, 2st. dopaminergen Neurone

81 IZN Teaching Program

S Progress Report der Lectures/Courses/Seminars winter term Arbeitsgruppe (in englischer Sprache), 2st. 2002/03 S Journal Club (in englischer H. Monyer, W. Wisden und Sprache), 1st. Mitarbeiter

S Forschergruppen-Seminar K. Unsicker und V Biologie III, 5st. (Teil B. Dobberstein, H. Bading, ‘Zentrale aminerge Systeme Teilprojektleiter der Zellbiologie) H.-H. Gerdes, D. Görlich, und Mechanismen’, 2st Forschergruppe D. Robinson S Seminar “Anatomie”, 2st. W. Kriz, K. Unsicker, V Verwendung von Software H. Simon, R. Mosbach S. Angermüller, K. Gorgas, und Datenbasen in der S. Mense, J. Metz, Molekular Biologie, 2st. K. Tiedemann, A. Völkl, V Makroskopische Anatomie, 6 K. Unsicker, S. Angermüller, K.H. Endlich, R. Kinscherf, st. K. Gorgas, S. Mense, J. Metz, R. Witzgall, K. Zaar, D. Hock K. Tiedemann, A. Völkl, GP+, Grundpraktikum C4, H.-H. Gerdes, U. Ernsberger, K.-H. Endlich, R. Kinscherf K Physiologie, 5st. T. Euler, R. Friedrich V Mikroskopische Anatomie K. Unsicker, S. Angermüller, HP-B Praktikum: Moderne H. Bading, R. Brandt, und Zellbiologie, 4 st. K. Gorgas, J. Kartenbeck, Methoden in der T. Euler, H.-H. Gerdes, A. S. Mense, J. Metz, Neurobiologie, 3wö., Herb, H. Monyer, W. Wisden K. Tiedemann, A. Völkl, ganztäg., (HF, NF, K.-H. Endlich, R. Kinscherf Sachgruppe III) V Neurologie/Neuroradiologie/ W. Hacke, S, Kunze, K. Sartor, HP-C Laborpraktikum H. Bading, R. Brandt, Neurochirurgie, 2st. H.-M. Meinck, H. Monyer und Neurobiologie, 6wö., H.-H. Gerdes, N.N. Mitarbeiter ganztäg. S Einführung in die Biologie O. Bräunling, F. Ciccolini K Makroskopisch- W. Kriz, K. Unsicker, (für 1. Semester), 2st. Anatomischer Kurs, S. Angermüller, K. Gorgas, S Einführung in die Zellbiologie H.-H. Gerdes, W. Wisden Abschnitte 4 und 5, S. Mense, J. Metz, (für 1. Semester), 2st. scheinpflichtig, 8st. K. Tiedemann, A. Völkl, K.H. Endlich, R. Kinscherf, N. S Einführung in die molekulare H. Bading, F. Ciccolini, Endlich, K. Huber, Zellbiologie (für 3. H.-H. Gerdes, A. Régnier- D. Hock, H. Peterziel, Semester), 2st. Vigouroux, W. Wisden J. Strelau, W.P. Trudrung, S Entwicklungsneurobiologie H. Bading, H.-H. Gerdes, N.N., N.N. H. Simon, K. Unsicker, K Kurs der Mikroskopischen W. Kriz, K. Unsicker, K.-A. Nave Anatomie, zweiter Teil, S. Angermüller, K. Gorgas, S Molecular Mechanisms of J. Wittbrodt scheinpflichtig, 4st. J. Kartenbeck, S. Mense, Organogenesis, HF J. Metz, K. Tiedemann, FS IZN Seminar: Progress in H. Bading, H. Monyer, A. Völkl, K.H. Endlich, Neurosciences (for members K. Unsicker and the U. Ernsberger, R. Kinscherf, of the IZN und interested groupleaders of the IZN N. Endlich, D. Hock, C. Otto, students, in English), 1st. H. Peterziel, W.P. Trudrung, J. Tu ckermann, J. Strelau, N.N., N.N.

82 IZN Teaching Program

S Neurobiology Lectures with U. Ernsberger, W. Wisden and HP- Laborpraktika: Moderne H. Bading, F. Ciccolini, H.-H. invited speakers (for the groupleaders of the IZN L Methoden in der Gerdes, W. Wisden members of the IZN und Neurobiologie, 6-wöchig, interested students, in ganztägig English), 1st. HP- Anti-tumour immunity in the A. Régnier-Vigouroux LS Journal Club Neurobiology Members of Neurobiology L brain (in English), 2st. K Makroskopisch-Anatomischer W. Kriz, K. Unsicker, S. FS Mitarbeiterseminar: Neuronal H. Bading und Mitarbeiter Kurs, erster Teil, Angermüller, K. Gorgas, S. Plasticity (in English), 2st. scheinpflichtig, 8st. Mense, J. Metz, K. FS Mitarbeiterseminar: Neuronal R. Brandt und Mitarbeiter Tiedemann, A. Völkl, K.H. Cytoskeleton (in englischer Endlich, R. Kinscherf, N. Sprache), 2st. Endlich, D. Hock, H. Peterziel, FS Mitarbeiterseminar: Neural F. C i ccolini and Mitarbeiter J. Strelau, K. Schindowski, O. Stem Cells (in English), 2st. von Bohlen und Halbach, W.P. Tr udrung, N.N., N.N. FS Mitarbeiterseminar: Sekretion H.-H. Gerdes und Mitarbeiter von Neuropeptiden (in K Kurs der Mikroskopischen W. Kriz, K. Unsicker, S, English), 2st. Anatomie, erster Teil, Angermüller, K. Gorgas, J. scheinpflichtig, 4st. Kartenbeck, S. Mense, J. FS Mitarbeiterseminar: TGF- K. Unsicker und Mitarbeiter Metz, K. Tiedemann, A. Völkl, Betas (in English), 2st. K.H. Endlich, U. Ernsberger, R. LS Journal Club für Mitarbeiter K. Unsicker und Mitarbeiter Kinscherf, N. Endlich, D. der Neuroanatomie (in Hock, C. Otto, H. Peterziel, K. englischer Sprache), im Schindowski, O. von Bohlen Wechsel mit und Halbach, A. Schober, W.P. Mitarbeiterseminar, 2st. Tr udrung, Tuckermann, J. FS Mitarbeiterseminar: H. Simon und Mitarbeiter Strelau, N.N., N.N. Entwicklung der Mittelhirn dopaminergen Neurone FS Progress Report der H. Monyer, W. Wisden und Arbeitsgruppe (in englischer Mitarbeiter Sprache), 2st. LS Journal Club (in englischer H. Monyer, W. Wisden und Sprache), 1st. Mitarbeiter S SFB 488 Seminar ‘Molekulare K. Unsicker und und zelluläre Grundlagen Teilprojektleiter des SFB 488 neuraler Entwicklungsprozesse’, 2st. FS Forschergruppen-Seminar K. Unsicker und ‘Zentrale aminerge Systeme Teilprojektleiter der und Mechanismen’, 2st. Forschergruppe HP- Cellbiology E2 (Biochemistry H. Bading, O. Bräunling, H.- E - Morphology) 3-weekly, full H. Gerdes, A. Régnier- day, (HF, NF, LA Sachgruppe Vigouroux, W. Wisden III)

Appendix

Publications of IZN members, 2001-2002

Publications of IZN members, 2001-2002 • Bading, H. (2000) Transcription-dependent neuronal plasticity: the nuclear calcium hypothesis. Hilmar Bading Eur. J. Biochem. 267: 5280-5283. • Hardingham, G.E., Bading, H. (2003) Peer-reviewed publications The ying and yang of NMDA receptor signalling. Trends in Neurosci., in press. • Hardingham, G.E., Arnold, F.J.L., Bading, H. (2001) Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity. Roland Brandt Nature Neuroscience 4: 261-267.

• Lange, C., Bading, H. (2001) Peer-reviewed publications The role of putative intragenic control elements in c-fos • Brandt, R. (2001) regulation by calcium and growth factor signalling pathways. Cytoskeletal mechanisms of neuronal degeneration. J. Neurochem. 77: 1293-1300. Cell & Tissue Res. 305: 255-265. • Hardingham, G.E., Arnold, F.J.L., Bading, H. (2001) • Eidenmüller, J., Fath, T., Maas, T., Pool, M., Sontag, E., Brandt, R. A calcium microdomain near NMDA receptors: on-switch for (2001) ERK-dependent synapse-to-nucleus communication. Phosphorylation-mimicking glutamate cluster in the proline- Nature Neuroscience 4: 565-566. rich region are sufficient to simulate functional deficiencies of • Chawla, S., Bading, H. (2001) hyperphosphorylated tau protein. CREB/CBP and SRE-interacting transcriptional regulators are Biochem. J. 357: 759-767. fast on-off switches: duration of calcium transients specifies the • Piontek, J., Régnier-Vigouroux, A., Brandt, R. (2002) magnitude of transcriptional responses. Contact with astroglial membranes induces axonal and J. Neurochem. 79: 849-858. dendritic growth of human CNS model neurons and affects the • Hardingham, G.E., Fukunaga, Y., Bading, H. (2002) distribution of the growth-associated proteins MAP1B and Extrasynaptic NMDARs oppose synaptic NMDARs by triggering GAP43. CREB shut-off and death pathways. J. Neurosci. Res. 67: 471-483. Nature Neuroscience 5: 405-415. • Klein, C., Kramer, E.-M., Cardine, A.-M., Schraven, B., Brandt, R., • Hardingham, G.E., Bading, H. (2002) Trotter, J. (2002) Coupling of extrasynaptic NMDA receptors to CREB shut-off Process outgrowth of oligodendrocytes is promoted by pathway is developmentally regulated. interaction of fyn kinase with the cytoskeletal protein tau. Biochim. Biophys. Acta, in press. J. Neurosci. 22: 698-707.

• Pokorska, A., Vanhoutte, P., Arnold, F.J.L., Silvagno, F., • Fath, T., Eidenmüller, J., Brandt, R. (2002) Hardingham, G.E., Bading, H. (2003) Tau-mediated cytotoxicity in a pseudohyperphosphorylation Synaptic activity induces signalling to CREB without increasing model of Alzheimer's disease. global levels of cAMP in hippocampal neurons. J. Neurosci. 22: 9733-9741. J. Neurochem. in press. • Shahani, N., Brandt, R. (2002) Reviews Functions and malfunctions of the tau proteins. Cell. Mol. Life Sci. 59: 1668-1680. • Cruzalegui, F. H., Bading, H. (2000) Calcium-regulated protein kinase cascades and their transcription factor targets. Cell. Mol. Life Sci. 57: 402-410.

87 Publications of IZN members, 2001-2002 Francesca Ciccolini Uwe Ernsberger Peer-reviewed publications Peer-reviewed publications

• Sudhoelter, J., Ciccolini, F., Zhang, W., Berridge, M. J., • Combs, S.E., Ernsberger, U., Krieglstein, K., Unsicker, K. Bootman, M.D., Lipp, P. (2000) (2001) Characterisation of neurosphere-derived neuronal precursor Reduction of endogenous TGF-ß does not affect phenotypic cells from E14 mouse striatum. development of sympathoadrenal progenitors into adrenal J. Physiol. 523P, pp. 197 P. chromaffin cells. Mech. Dev. 109: 295-302. • Ciccolini, F., Collins, T., Berridge, M.J., Bootman, M.D., Lipp, P. (2000) • Patzke, H., Reissmann, E., Stanke, M., Bixby, J.L., Ernsberger, U. Localised and global spontaneous calcium events during neural (2001) precursor differentiation. BMP growth factors and Phox2 transcription factors can induce J. Physiol. 527P, pp. 103P. synaptotagmin I and neurexin I during sympathetic neuron development. • Giarre, M., Caldeira, S., Malanchi, I., Ciccolini, F., Leao, M.J., Tommasino, M. (2001) Mech. Dev. 10: 149-159. Induction of pRb degradation by the human papillomavirus • Huber, K., Brühl, B., Guillemot, F., Olson, E.N., Ernsberger, U., type 16 E7 protein is essential to efficiently overcome Unsicker, K. (2002) p16INK4a-imposed G1 cell cycle arrest. Development of chromaffin cells depends on MASH1 function. J. Virol. 75: 4705-12. Development 12: 4729-4738. • Ciccolini, F. (2001) Reviews Identification of two distinct types of multipotent neural precursors that appear sequentially during CNS development. • Ernsberger, U. (2001) Mol. Cell. Neurosci. 17: 895-907. The development of postganglionic sympathetic neurons: • Ciccolini, F., Svendsen, C.N. (2001) coordinating neuronal differentiation and specification. Neurotrophin responsiveness is differentially regulated in Auton. Neurosci. 94: 1-13. neurons and precursors isolated from the developing striatum. • Huber, K., Combs, S., Ernsberger, U., Kalcheim, C., Unsicker, K. J. Mol. Neurosci. 17: 25-33. (2002) • Ciccolini, F., Collins, T.J., Sudhoelter, J., Lipp, P., Berridge, M.J., Generation of neuroendocrine chromaffin cells from Bootman, M.D. (2003) sympathoadrenal progenitors: Beyond the glucocorticoid Local and global spontaneous calcium events regulate neurite hypothesis. outgrowth and onset of GABAergic phenotype during neural In „The chromaffin cell“, O’Connor, D.T., Eiden, L.E., eds.; precursor differentiation. Ann. NY Acad. Sci. 971: 101-102. J. Neurosci. 23: 103-111. • Ernsberger, U. (2003) Gene expression from precursor to mature neuron. Reviews In „ Molecular Biology of the Neuron“, 2nd ed; Davies, W., • Bootman, M.D., Collins, T.J., Peppiatt, C.M., Prothero, L.S., Morris, B., eds; Oxford University Press, Oxford, UK.,in press MacKenzie, L., De Smet, P., Travers, M., Tovey, S.C., Seo, J.T., Berridge, M.J., Ciccolini, F., Lipp, P. (2001) Siegfried Mense Calcium signalling-an overview. Sem. Cell Dev. Biol. 12: 3-10. Peer-reviewed publications

• Steffens, H., Hoheisel, U., Eek, B., Mense, S. (2001) Tetrodotoxin-resistant conductivity and spinal effects of

88 Publications of IZN members, 2001-2002

cutaneous C-fibre afferents in the rat. and human studies. Neuroscience Res. 39, 413-419. The Clin. J. Pain 17, 2-10.

• Blum, T., Hoheisel, U., Unger, T., Mense, S. (2001) • Mense, S. (2001) Fibroblast growth factor-2 acutely influences the impulse Pathophysiologie des Rückenschmerzes und seine activity of rat dorsal horn neurones. Chronifizierung. Tierexperimentelle Daten und neue Konzepte. Neuroscience Res., 40, 115-123. Der Schmerz 15, 413-417.

• Graven-Nielsen, T., Mense, S. (2001) • Mense, S., Hoheisel, U. (2002) The peripheral apparatus of muscle pain: Evidence from animal Mechanisms of skeletal muscle pain. In: Preedy, V.r., and human studies. Peters, T.J. (Eds.), Skeletal Muscle. Pathology, Diagnosis and The clin. J. Pain 17, 2-10. Management of Disease. Greewich Medical Media, London, 293- 300. • Mense, S. (2001): Pathophysiologie des Rückenschmerzes und seine Chronifizierung. • Mense, S. (2002) Tierexperimentelle Daten und neue Konzepte. Do we know enough to put forward a unifying hypothesis? Der Schmerz 15, 413-417. J. Pain 3,264-267.

• Scheifer, C., Hoheisel, U., Trudrung, P., Unger, T., Mense, S. (2002) Hannah Monyer Rats with chronic spinal cord transection as a possible model for the at-level-pain of paraplegic patients. Peer-reviewed publications Neurosci. Letters 323, 117-120. • Fuchs, E.C., Doheny, H., Faulkner, H., Caputi, A., Traub, R.D., • Graven-Nielsen, T., Arendt-Nielsen, L., Mense, S. (2002) Thermosensitivity of muscle: high-intensity thermal stimulation Bibbig, A., Kopell, N., Whittington, M.A., Monyer, H. (2001) of muscle tissue induces muscle pain in humans. Genetically altered AMPA-type glutamate receptor kinetics in J. Physiol. 540.2, 647-656. interneurons disrupt long-range synchrony of gamma oscillation. • Steffens, H., Eek, B., Trudrung, P., Mense, S. (2002) Proc. Natl. Acad. Sci. USA 98: 3571-3576. Tetrodotoxin block of A-fibre afferents from skin and muscle – A tool to study pure C-fibre effects in the spinal cord. • Hormuzdi, S.G., Pais, I., LeBeau, F.E.N., Towers, S.K., Rozov, A., Pflügers Arch.-Eur. J. Physiol.,in press. Buhl, E.H., Whittington, M.A., Monyer, H. (2001) Impaired Electrical Signalling Disrupts Gamma Frequency • Reinöhl, J., Hoheisel, U., Unger, T., Mense, S. (2002) Oscillations in Connexin 36 Deficient Mice. Adenosine triphosphate as a stimulant for nociceptive and Neuron 31: 487-495. non-nociceptive muscle group IV receptors in the rat. Neurosci. Lett., in press. • Kelsch, W., Hormuzdi, S., Straube, E., Lewen, A., Monyer, H., Misgeld, U. (2001) Reviews and book contributions Insulin-like growth factor 1 and a cytosolic tyrosine kinase activate chloride outward transport during maturation of • Mense, S. (2001) hippocampal neurons. Fondamenti patofisiologici del dolore musculare. J. Neurosci. 21: 8339-47. In: S. Palla (Hrsg.), Mioartropatie del sistema masticatorio e • Bartos, M., Vida, I., Frotscher, M., Meyer, A.H., Monyer, H., dolori orofaciali, pp. 89-117, RC libri srl, Milano. Geiger, J.R.P., Jonas, P. (2002) • Mense, S., Hoheisel, U. (2001) Fast synaptic inhibition promotes synchronized gamma Stickstoffmonoxid-Mangel im Rückenmark. Möglicher Faktor für oscillations in hippocampal interneuron networks. die Entstehung von Spontanschmerzen. Proc. Natl. Acad. Sci. USA 99: 13222-13227. Der Schmerz 15, 19-25. • Meyer, A.H., Katona, I., Blatow, M., Rozov, A., Monyer, H. • Graven-Nielsen, T., Mense, S. (2001) (2002) The peripheral apparatus of muscle pain: Evidence from animal In vivo labeling of parvalbumin-positive interneurons and

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analysis of electrical coupling in identified neurons. mice deficient in the RNA-editing enzyme ADAR2. J. Neurosci. 22: 7055-7064. Nature 406: 78-81.

• Blatow, M., Rozov, A., Katona, I., Meyer, A.H., Caputi, A., • Venance, L., Rozov, A., Blatow, M., Burnashev, N., Feldmeyer, D., Monyer, H. (2002) Monyer, H. (2000) A novel network of multipolar bursting interneurons connected Connexin expression in electrically coupled postnatal rat brain by chemical and electrical synapses. (submitted) neurons. Proc. Natl. Acad. Sci. U S A. 97:10260-10265. • Blatow, M., Caputi, A., Monyer, H., Burnashev, N., Rozov, A. (2002) • Rozov, A., Burnashev, N., Sakmann, B., Neher, E. (2001) Ca2+ buffer saturation underlies paired pulse facilitation at Transmitter release modulation by intracellular Ca2+ buffers in calbindin-D28K containing terminals. (submitted) facilitating and depressing nerve terminals of pyramidal cells in layer 2/3 of the rat neocortex indicates a target cell-specific Book Chapters, Reviews difference in presynaptic calcium dynamics. J. Physiol. 531: 807-826. • Monyer, H. (2001) Erinnern und Vergessen: Drei Mnemotechniker in der Literatur • Mack, V., Burnashev, N., Kaiser, K.M., Rozov, A., Jensen, V., des 20. Jahrhunderts. Hvalby, O., Seeburg, P.H., Sakmann, B., Sprengel, R. (2001) In Medizin & Kultur: Ärztliches Denken und Handeln im Dialog Conditional restoration of hippocampal synaptic potentiation zwischen Natur- und Geisteswissenschaften, eds. G Maio und V in Glur-Α-deficient mice. Roelcke, Schattauer, Stuttgart, 252-259. Science. 292: 2501-2504.

• Laurie, D.J., Schrotz, P.C.U., Monyer, H., Amtmann, U. (2002) • Hormuzdi, S.G., Pais, I., LeBeau, F.E., Towers, S.K., Rozov, A., Processing Rodent Embryonic and Early Postnatal Tissue for In Buhl, E.H., Whittington, M.A., Monyer, H. (2001) Situ Hybridization with Radiolabelled Oligonucleotides. Impaired electrical signaling disrupts gamma frequency In: International Review of Neurobiology, Vol 47, In Situ oscillations in connexin 36-deficient mice. Hybridization Protocols for the Brain, 2nd Edition, eds. Neuron 31: 487-495. W. Wisden and B.J. Morris, Academic Press, London, 71-83. • Rozov, A., Jerecic, J., Sakmann, B., Burnashev, N. (2001) AMPA receptor channels with long-lasting desensitization in • Gerfin-Moser, A., Monyer, H. (2002) In Situ Hybridization on Organotypic Slice Cultures. bipolar interneurons contribute to synaptic depression in a In: International Review of Neurobiology, Vol 47, In Situ novel feedback circuit in layer 2/3 of rat neocortex. J. Neurosci. 21 : 8062-8071. Hybridization Protocols for the Brain, 2nd Edition, eds. W. Wisden and B.J. Morris, Academic Press, London, 125-134. • Sansig, G., Bushell, T.J., Clarke, V.R., Rozov, A., Burnashev, N., Portet, C., Gasparini, F., Schmutz, M., Klebs, K., Shigemoto, R., Flor, P.J., Kuhn, R., Knoepfel, T., Schroeder, M., Hampson, D.R., Andrei Rozov Collett, V.J., Zhang, C., Duvoisin, R.M., Collingridge, G.L., van Der Putten, H. (2001) Peer-reviewed publications Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7. • Single, F.N., Rozov, A., Burnashev, N., Zimmermann, F., J. Neurosci. 21: 8734-8745. Hanley, D.F., Forrest, D., Curran, T., Jensen, V., Hvalby, O., Sprengel, R., Seeburg, P.H. (2000) • Meyer, A.H., Katona, I., Blatow, M., Rozov, A., Monyer, H. Dysfunctions in mice by NMDA receptor point mutations (2002) NR1(N598Q) and NR1(N598R). In vivo labeling of parvalbumin-positive interneurons and J. Neurosci. 20: 2558-2566. analysis of electrical coupling in identified neurons. J. Neurosci. 22: 7055-7064. • Higuchi, M., Maas, S., Single, F.N., Hartner, J., Rozov, A., Burnashev, N., Feldmeyer, D., Sprengel, R., Seeburg, P.H. (2000) Point mutation in an AMPA receptor gene rescues lethality in

90 Publications of IZN members, 2001-2002 Reviews Jacqueline Trotter • Burnashev, N., Rozov, A. (2000) Peer-reviewed publications Genomic control of receptor function. Cell. Mol. Life Sci. 57: 1499-1507. • Schneider, S.S., Niehaus, A., Bosse, F., D`Urso, D., Müller, H-W., Sereda, M., Nave, K-A., Niehaus, A., Trotte r, J. (2001) Horst Simon The AN2 protein is a novel marker for the Schwann cell lineage expressed by immature and non-myelinating Schwann cells. Peer-reviewed publications J. Neurosci. 21, 920-933. • Ruhl, A., Trotter, J. , Stremmel, W. (2001) • Simon, H.H., Saueressig, H., Wurst, W., Goulding, M.D., Isolation of enteric glia and establishment of transformed O’Leary, D.D.M. (2001) enteroglial cell lines from the myenteric plexus of adult rat. Fate of midbrain dopaminergic neurons is controlled by Neurogastroenterol. Motil. 13, 95-106. engrailed-1 and –2. • Diers-Fenger, M., Kirchhoff, F., Kettenmann, H. Levine, J.M. J. Neurosci. 21 (9) 3126-34. Trotte r, J . (2001) • Thuret, S., Gassmann, M., Lloyd, K., Klein, R., Dyck, R.H., AN2/NG2 protein-expressing glial progenitor cells in the Simon, H.H. murine CNS: isolation, differentiation and association with Expression of the neuregulin receptor, ErbB4, is not required radial glia. for normal development of the substantia nigra. Glia 34: 213-228. Submitted. • Klein, C., Krämer, E-M., Marie-Cardine, A., Schraven, B., • Simon, H.H., Scholz, C., Döderlein, G. Brandt, R., Trotter, J . (2002) Genome Sequencing Data: Fast, one step cloning of defined Process outgrowth of oligodendrocytes is promoted by genomic DNA Fragments from identified TIGR BAC clones. interaction of Fyn kinase with the cytoskeletal protein Tau. Nucl. Acid. Res. Submitted. J. Neurosci. 22: 698-707.

• Thuret, S., Kaestner, K., Simon, H.H. • Simons, M., Kramer, E.M., Macchi, P., Rathke-Hartlieb, S., The expression of the forkhead transcription factor, HNF3α, is Trotte r, J . , Nave, K-A., Schulz, J.B. (2002) highly restricted in the mammalian brain to the midbrain Overexpression of the myelin proteolipid protein leads to dopaminergic neurons. accumulation of cholesterol and proteolipid protein in Submitted. endosomes/lysosomes: implications for Pelizaeus-Merzbacher • Alberi, L., Scholz, C., Thuret, S., Logan, C., Simon, H.H. disease. The engrailed transcription factors are cell autonomously J. Cell Biol. 157: 327-36. required for the survival of the midbrain dopaminergic neurons. • Stegmüller, J., Werner, H., Nave, K-A., Trotte r, J . Submitted. The proteoglycan NG2 is complexed with AMPA receptors by the PDZ protein GRIP in glial progenitor cells: implications for Reviews glial-neuronal signalling. J. Biol. Chem. in press. • Simon, H.H., Bhatt, L., Gherbassi, D., Sgadó, P., Alberí, L. (2002) Reviews The midbrain dopaminergic neurons: Determination of their developmental fate by transcription factors. • Stegmüller, J., Schneider, S.S., Hellwig, A., Garwood, J.G., Ann. N.Y. Acad. Sci in press. Trotte r J . AN2, the mouse homologue of NG2, is a surface antigen on glial precursor cells implicated in control of cell migration. J. Neurocytology, special issue on NG2, invited review.

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Kerry L. Tucker growth factor-2 on cultured midbrain dopaminergic neurons. Mol. Cell. Neurosci. 18: 44-55. Peer-reviewed publications • Combs, S.E., Ernsberger, U., Krieglstein, K., Unsicker, K. (2001) Reduction of endogenous TGF-ß does not affect phenotypic • Tucker, K. L., Meyer, M., Barde, Y.-A. (2001) development of sympathoadrenal progenitors into adrenal Neurotrophins are required for nerve growth during chromaffin cells. development. Mech. Dev. 109; 295-302. Nature Neuroscience 4: 29-37. • Schober, A., Böttner, M., Strelau, J., Kinscherf, R., Bonaterra, A., • Wernig, M., Tucker, K. L., Gornik, V., Schneiders, A., Barth, M., Schilling, L., Fairlie, D., Breit, S., Unsicker, K. (2001) Buschwald, R., Wiestler, O. D., Barde, Y.-A., Bruestle, O. (2002) Expression of Growth/Differentiation Factor-15/Macrophage Ta u EGFP embryonic stem cells: An efficient tool for neuronal Inhibitory Protein-1 (GDF-15/MIC-1) in the perinatal, adult lineage selection and transplantation. and injured brain. J. Neurosci. Res. 6: 918-924. J. Comp. Neurol. 439: 32-45.

• Heins, N., Malatesta, P., Cecconi, F., Nakafuku, M., Tucker, K.L., • Reuss, B., Unsicker, K. (2001) Hack, M., Chapouton, P., Barde, Y.-A., Goetz, M. (2002) Atypical neuroleptic drugs downregulate dopamine sensitivity Glial cells generate neurons. the role of the transcription factor in rat cortical and striatal astrocytes. Pax6. Mol. Cell. Neurosci. 18: 197-209. Nature Neuroscience 5: 308-315. • Grunwald, I.C., Korte, M., Wolfer, D., Wilkinson, G.A., Reviews Unsicker, K., Lipp, H.-P., Bonhoeffer, T., Klein, R. (2001) A kinase-independent requirement of EphB2 receptors in • Tucker, K. L. (2001) hippocampal synaptic plasticity and spatial learning. In vivo imaging of the mammalian nervous system using Neuron 32: 1027-1040. fluorescent proteins. • Reuss, B., Unsicker, K. (2001) Histochem. Cell Biol. 115: 31-39. Dopamine and epinephrine, but not serotonin, downregulate • Tucker, K. L. (2001) dopamine sensitivity in cultured cortical and striatal astroglial Methylated cytosine and the brain: A new base for cells. neuroscience. Receptors & Channels 7: 441-45. Neuron 30: 649-652. • Leung, D.S.Y., Unsicker, K., Reuss, B. (2002) • Tucker, K. L. (2002) Expression and developmental regulation of gap junction Neurotrophins and the control of axonal outgrowth. connexins cx26, cx32, cx43 and cx45 in the rat midbrain floor. Panminerva Medica 44: 325-333. Int. J. Dev. Neurosci. 20: 63-75.

• Lenhard, T., Schober, A., Suter-Crazzolara, C., Unsicker, K. Klaus Unsicker (2002) Fibroblast growth factor-2 requires glial cell line-derived Peer-reviewed publications neurotrophic factor for exerting its neuroprotective actions on glutamate-lesioned hippocampal neurons. • Roosen, A., Schober, A., Strelau, J., Böttner, M., Faulhaber, J., Mol. Cell. Neurosci. 20: 181-197. Bendner, G., McIlwrath, S.L., Seller, H., Ehmke, H., Lewin, G.R., • Okun, J.G., Hörster, F., Farkas, L.M., Feyh, P., Hinz, A., Auer, S., Unsicker, K. (2001) Hoffmann, G.F., Unsicker, K., Mayatepek, E., Kölker, S. (2002) Lack of NT-4 causes selective structural and chemical deficits in Neurodegeneration in methylmalonic aciduria involves sympathetic ganglia and their preganglionic innervation. inhibition of complex II and the tricarboxylic acid cycle, and J. Neurosci. 21: 3073-3084. synergistically acting excitotoxicity. • Leung, D.S.Y., Unsicker, K., Reuss, B. (2001) J. Biol. Chem. 277: 14674-14680. Gap junctions modulate survival-promoting effects of fibroblast

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• Huber, K., Brühl, B., Guillemot, F., Olson, E.N., Ernsberger, U., Submitted Unsicker, K. (2002) Development of chromaffin cells depends on MASH-1 function. • DiNardo, A., Gareus, R., Perlas, E., Unsicker, K., Sassoe- Development 129: 4729-4738. Pognetto, M., Panzanelli, P., Kneussel, M., Dotti, C., Witke, W. (2002) • Peterziel, H., Unsicker, K., Krieglstein, K. (2002) In profilin 2 mutant mice refractory stress response and lack of Molecular mechanisms underlying the cooperative effect of maternal behavior correlates with deregulated neuronal glial cell line-derived neurotrophic factor and transforming membrane recycling. growth factor beta in neurons. Science, submitted. J. Cell Biol. 159: 157 - 167. • Farkas, L.M., Dünker, N., Roussa, E., Unsicker, K., Krieglstein, K. • Schlittenhardt, D., Schober, A., Strelau, J., Traut, U., Schmiedt, (2003) W., Unsicker, K., Metz, J., Kinscherf, R. (2002) TGF-ßs are essential for the development of midbrain Growth differentiation factor-15/Macrophage inhibitory dopaminergic neurons in vitro and in vivo. cytokine-1 (GDF-15/MIC-1) immunoreactivity in oxidatively J. Neuroscience, submitted and revised. stressed, apoptotoic macrophages of human atherosclerotic carotid arteries. • Reuss, B., Unsicker, K.(2002) J. Leucocyte Biol., in press. Dopamine differentially regulates functional coupling and connexin43 expression in cortical and striatal neonatal rat • Specht, H., Peterziel, H., Bajohrs, M., Gerdes, H.-H., Krieglstein, astroglial cultures. K., Unsicker, K. (2002) Neuroscience Lett., submitted. TGF-ß2 is released from PC12 cells via the regulated pathway of secretion. • Oberle, S., Schober, A., Meyer, V., deLapeyrière, O., Henderson, Mol. Cell Neurosci., in press. Ch., Holtmann, B., Sendtner, M., Unsicker, K. (2002) Loss of leukemia inhibitory factor receptor ß causes severe • Bohlen, O.v., Unsicker, K. (2002) deficits in the pre- and postganglionic sympathetic nervous Morphological alterations in the amygdala and hippocampus of system. mice during aging. J. Neuroscience, submitted. Eur. J. Neuroscience 16: 2434-2440 • Subramaniam, S., Strelau, J., Unsicker, K.(2003) Reviews/Book Chapters Growth/differentiation factor-15 prevents low potassium induced cell death of cerebellar granule neurons by differential • Schober, A., Krieglstein, K., Unsicker, K. (2001) regulation of Akt and ERK pathways. Neurotrophins, the chromaffin system, and preganglionic J. Biol. Chem., in press (online as M210037200). sympathetic neurons. In: Neurobiology of the Neurotrophins (I. Mocchetti, ed.), pp. • Bohlen, O.v., Unsicker, K. (2002) 18 9-204. FP Graham Publishing Co, Johnson City, TN. Age-related decline in the catecholaminergic innervation of the amygdala and dentate gyrus in mice. • Schober, A., Unsicker, K. (2001) Cell Tiss. Res., in press. Growth and Neurotrophic Factors regulating development and Maintenance of Sympathetic Preganglionic Neurons. • Allmendinger, A., Stoeckel, E., Saarma, M.,Unsicker, K., Huber, Int. Review Cytol. 205: 37-76. K. (2002) Development of adrenal chromaffin cells is largely normal in • Krieglstein, K., Strelau, J., Schober, A., Sullivan, A., Unsicker, K. mice lacking the receptor tyrosine kinase c-Ret. (2001) Mech. Dev., in press. TGF-ß and the regulation of neuron survival and death. J. Physiol. (Paris) 96: 25-30. • Reuss, B., Dono, R., Unsicker, K. (2003) Functions of FGF-2 and FGF-5 in astroglial differentiation and • Kalcheim, C., Langley, K., Unsicker, K. (2002) blood brain barrier permeability: Evidence from mouse mutants. From the neural crest to chromaffin cells: Introduction to a J. Neuroscience, in press. session on chromaffin cell development. Ann. NY Acad. Sci., Volume „The chromaffin cell: transmitter

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biosynthesis, storage, release, actions, and informatics“ • Wisden, W., Cope, D., Klausberger, T., Hauer, B., (O´Connor, D., Eiden, L., eds), in press. Sinkkonen, S.T., Tretter, V., Lujan, R., Jones, A., Korpi, A.,

• Huber, K., Combs, S., Ernsberger, U., Kalcheim, C., Unsicker, K. Mody, I., Sieghart, W., Somogyi, P. (2002) α (2002) Ectopic expression of the GABAA receptor 6 subunit in Generation of neuroendocrine chromaffin cells from hippocampal pyramidal neurons produces extrasynaptic sympathoadrenal progenitors: beyond the glucocorticoid receptors and an increased tonic inhibition. hypothesis. Neuropharmacology 43, 530-549. Ann. NY Acad. Sci., Volume „The chromaffin cell: transmitter • Aller, M.I., Jones, A., Merlo, D., Paterlini, M., Meyer, A.H., biosynthesis, storage, release, actions, and informatics“ Amtmann, U., Brickley, S., Jolin, H.E., McKenzie, A.N.J., (O´Connor, D., Eiden, L., eds), in press. Monyer, H., Farrant, M., Wisden, W. (2003) • Unsicker, K., Krieglstein, K. (2002) Cerebellar granule cell Cre recombinase expression. TGF-ßs and their roles in the regulation of neuron survival. genesis (in press subject to minor revision). In: Molecular and Cellular Biology of Neuroprotection in the CNS (Alzheimer, C., ed). Landes Bioscience, chapter 14. Special Reviews

• Strelau, J., Unsicker, K. (2002) • Wisden, W., Morris, B.J. (2002) Neuroregeneration. In situ hybridization with oligonucleotide probes. Chapter 1 in Advances of Neurology, in press. In Situ Hybridization Protocols for the Brain. Editors: W. Wisden and B.J. Morris. International Review of Neurobiology, 47, 3-59 William Wisden Updated and extended version for 2nd edition of Wisden and Morris, 1994. Peer-reviewed publications General Reviews/book chapters • Brickley, S.G., Revilla, V., Cull-Candy, S.G., Wisden, W., • Wisden, W., Farrant, M. (2001) Farrant, M. (2001) Insights into GABA receptor complexity form the study of Adaptive regulation of neuronal excitability by a voltage- A cerebellar granule cells: synaptic and extrasynaptic receptors. In + independent K conductance. Glutamate and GABA Receptors and Transporters: Structure, Nature 409, 88-92. Function and Pharmacology (Egebjerg, J., Schousboe, A., • Campos, M.L., de Cabo, C., Wisden, W., Juiz, J.M., Merlo, D. Krogsgaard-Larsen, P., eds) Taylor & Francis Group., 189-201. (2001) • Wisden, W. Morris, B.J. (2002) Expression of GABAA receptor subunits in brain stem auditory Introduction: Studying gene expression in neural tissues by in pathways: cochlear nuclei, superior olivary complex, and situ hybridization. Pp, xvii-xxi. Rewritten version for In Situ nucleus of the lateral lemniscus. Hybridization Protocols for the Brain, 2nd edition. Editors: W. Neuroscience 102 , 625-638. Wisden and B.J. Morris. International Review of Neurobiology, • Bedford, F.K., Kittler, J.T., Muler, E., Thomas, P., Uren, J.M., Volume 47. Merlo, D., Wisden, W., Triller, A., Smart, T.G., Moss, S.J. (2001) GABAA cell surface number and subunit stability are regulated by the ubiquitin protein Plic-1. Nature Neuroscience 4, 908-916.

• Lauder, A.J., Jolin, H.E., Smith, P., Smith, P., Jones, A., Wisden, W., Fallon, P.G., McKenzie, A.N.J. (2002) Multi-organ autoimmunity and lymphomagenesis result from over-expression of interleukin (IL)-9 and are differentially dependent on Th2 cytokine expression. (submitted).

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Symposia and Seminars Symposia and Seminars

IZN Seminars Alfred Stranzl, Monyer group 2001 Point mutations in AMPA receptors that affect short-term plasticity in GABAergic interneurons Mascha Blatow, Monyer group Jens Strelau, Unsicker group Synaptic plasticity and Ca2+ - buffers in a new type Expression of GDF-15/MIC-1 in the perinatal, of interneuron adult and injured rat brain Lorena Esposito, Ernsberger group Karsten Thelen, Pollerberg group Segregating neuronal and endocrine development The L1 cytoplasmic domain regulates neuronal in the sympathoadrenal system migration, signaling, and cytoskeletal interactions Anne Herb, Monyer group Sandrine Thuret, Simon group Molecular and functional characterization of NMDA Identification of genes expressed in the receptor subunit composition dopaminergic neurons of the substantia nigra and ventral tegmentum Istvan Katona, Monyer group Molecular determinants controlling network activity Peter Trudrung, Mense group Effects of chronic pathophysiological alterations on Nina Lüdemann, Brandt group the behaviour and spinal cord NL6 – a novel antibody which recognizes a immunohistochemistry in rats glycosylated epitope on neurofilament protein M Bill Wisden Heike Peterziel, Unsicker group Defining the role of neuronal circuits: fast, Release of TGF-ß2 via the regulated pathway of reversible regulation of selected cell types secretion Jörg Piontek, Brandt group 2002/2003 Organization of neuronal signaling complexes by gravin Stephan Oberle, Unsicker group Rana Roy, Langosch group Neurotrophic factors regulating development and Does SNARE-transmembrane segment play a role maintenance of preganglionic sympathetic neurons in membrane fusion? Rüdiger Rudolf, Gerdes group Amin Rustom, Gerdes group Motorizing maturation? „On the role of myosin Va Selective delivery of secretory cargo in Golgi- in the life of a secretory granule“ derived carriers reveals cognate sorting principles Daniel Gherbassi, Simon group in polar and non-polar cells How are the midbrain dopaminergic axons directed Bernhard Reuss, Unsicker group towards the basal ganglia? GFAP and Connexin 43 are region-specifically Siegfried Mense reduced in the brain of FGF-2 / FGF-5 double- Abnormal discharges in spinal neurones as an mutant mice explanation for chronic pain in patients with spinal Thorsten Salm, Gerdes group cord injury Recrutiment of myosin Va to SG – a matter of time? Mikhail Filippov, Monyer group Paola Sgadò, Simon group Investigation of Connexin26 gene expression using Pbx1, an atypical homeodomain transcription reporter mice factor , and the midbrain dopaminergic neurons Peer Wulff, Wisden group Neelam Shahani, Brandt group Selective neuronal silencing MINUS: A negative regulator of microtubule assembly in neurons (?)

96 Symposia and Seminars

Sandrine Thuret, Simon group Oliver von Bohlen und Halbach, Unsicker group Identification and characterization of genes Morphological alterations in the hippocampus and expressed by the midbrain dopaminergic neurons amygdala of aged mice Sergei Kuznetsov, Gerdes group Roberto Bruzzone, Monyer group Motor proteins in fast axonal transport The molecular and functional diversity of connexins Uwe Ernsberger in the vertebrate retina Cholinergic differentiation in sympathetic neurons Peter Vanhoutte, Bading group – revising a classical model of neuronal Glutamate receptor trafficking triggers changes in diversification neuronal network properties Antonio Caputi, Monyer group Uwe Ernsberger /Ernsberger-Unsicker cooperation Generation and analysis of Calretinin-EGFP Reconsidering sympathoadrenal beliefs transgenic mice Lavinia Bhatt, Simon group Amin Rustom, Gerdes group Genes essential for survival of the midbrain „Piggy-back“ transport of Xenopus hyaluronan dopaminergic neurons synthase via the secretory pathway to the plasma Christine Bark, Monyer group membrane Ultrastructural analysis of the connexin 36-EGFP Christine Winterstein, Trotter group mouse in the olfactory bulb Trafficking of myelin proteins and lipids Lavinia Alberi, Simon group Zsofia Sebö, Brandt group Cell autonomous requirement of the Engrailed Functional analysis of a tau-mutant (R406W) and genes for the survival of the midbrain dopaminergic its role in the neurodegenerative disease FTDP-17 neurons Andrei Rozov Bernhard Reuss, Unsicker group Presynaptic mechanisms of short-term synaptic Reduced levels of GFAP and a leaky blood brain enhancement barrier in mice deficient for FGF-2 and FGF-5 alone Elke Fuchs, Monyer group or in combination Changing AMPA-receptor function in GABAergic Ulrich Hoheisel, Mense group interneurons The significance of purinergic and vallinoid Nina Lüdemann, Brandt group receptors for the induction of muscle pain NL6 – a new antibody to analyse development of human neurons Srinivasa Subramaniam, Unsicker group GDF-15/MIC-1 protects cultured rat cerebellar granule neurons from cell death via the phosphatidylinositol-3 kinase pathway Irina Coserea, Monyer group Excitotoxicity in transgenic mice models Isabel Aller, Wisden group Gene-specific deletions in cerebellar granule cells Sheriar Hormuzdi, Monyer group Cx36 – Orchestrating synchrony in specific inhibitory circuits

97 Symposia and Seminars

SFB 488 Friday Seminars Irene Wacker 2001 C. elegans zag-1, a zinc finger homeobox transcription factor involved in axon guidance Roland Brandt Jochen Wittbrodt Cytoskeletal mechanisms of neuronal Molecular and genetic mechnisms controlling morphogenesis vertebrate eye development Dirk Feldmeyer Cajal-Retzius Zellen im Neokortex: Neue Ergebnisse 2002 zur Morphologie und Physiologie Rainer Friedrich Evi Albers Dynamics of odor processing in the zebrafish Vesicular traffic in myelinating oligodendrocytes olfactory bulb Stefan Berger Chaya Kalcheim Analysis of corticosteroid signaling in the brain by Regulation and function of the interaction between gene targeting BMP and noggin during neural crest and somite Dirk Feldmeyer development Cajal-Retzius cells in the neocortex of the reeler Clemens Kiecker mutant mouse A gradient of Wnt signalling regulates Sheriar Hormuzdi anteroposterior neural patterning in Xenopus Characterization of gap junction-communicative Corinna Klein neuronal circuits Linking up with the cytoskeleton: The role of Fyn Katrin Huber and Tau during early events of myelination Development of the sympathoadrenal lineage Rüdiger Klein Nina Lüdemann Distinct requirements for TrkB and TrkC signaling NL6 - a new antibody to analyze glycosylation and for target innervation of sensory neurons development of human neurons Dr. Thomas Lemberger Stefan Offermanns Brain-specific disruption of CREB function leads to Regulation of RhoA in neurons: The role of specific neuronal death and neurodegeneration RhoGEFs G. Elisabeth Pollerberg Christoph Peter The role of microtubule-associated protein MAP1B Construction of structurally intact but functionally in steering growth cones silent AChR complexes: A tool to analyze activity- Friedrich Reinhard dependent synapse formation Presenilin complex formation Oliver Schlicker Daniel Spergel GABAA receptors on the move GABA and Glutamate Receptor-Mediated Signaling Peter Soba in Hypothalamic GnRH Neurons APP and Notch signaling Mathias Treier Karsten Thelen Signaling pathways regulating pituitary Two members of the IgCAM family, L1 and DM- organogenesis GRASP, modulate neuronal migration and axonal Klaus Unsicker pathfinding Recent developments in the development of the Wei Wu neuroendocrine progeny of sympathoadrenal cells Dkk2 and Dkk1 function antagonistically during Wnt signalling 98 Symposia and Seminars

Heidelberg Neurobiology Lectures Wolfgang Driever, Freiburg 2001 Genetic analysis of the isthmic organizer and dopaminergic differentiation in zebrafish Christian Behl, München Eberhard Fuchs, Göttingen The Female Sex Hormone Estrogene and Stressful experiences: Their effects for brain Intracellular Signaling in Neuroprotection structure and function Christian Kaltschmidt, Witten/Herdecke Martyn Goulding, La Jolla Signaling via NF-kB in the nervous system Wiring Up Interneurons in the Spinal Cord: The Arthur Konnerth, München Connection Between Embryo and Adult Neurotrophin-evoked excitation in central neurons Ingo Greger, New York Andrew Matus, Basel RNA editing determines AMPA receptor trafficking. Analysis of synaptic plasticity using GFP-labeled A novel role for the Q/R editing site. proteins of the actin cytoskeleton Reinhard Köster, Pasadena T.R. Raju, Bangalore, India Intravital characterization of neuronal migration Neuronal Plasticity - Progressive and regressive Hans-Christian Pape, Magdeburg changes in the CA3 Pyramidal Neurons of the Neural correlates of fear behavior and fear memory Hippocampus in the amygdala Christine Richter-Landsberg, Oldenburg Christoph Schuster, Tübingen Stress response in oligodendrocytes: Implications Molecular Mechanisms of Long-Term Neuronal for neurodegenerative diseaeses Plasticity: Insights from a Glutamatergic Model Estelle Sontag, Texas, USA Synapse Protein phosphatase 2A: The Trojan Horse of Cornelius Schwarz, Tübingen cellular signaling Connecting Two Different Worlds. The Functional Walter Stuehmer, Göttingen Architecture of the Cerebro-cerebellar Pathway Visualizing the Last Steps in Exocytosis Werner Sieghart, Wien Structure and function of GABAA receptor 2002 subtypes Steven Skaper, Harlow, UK Matthias Bähr, Göttingen Neurotrophins and neuro-immune system Molecular basis of neural repair strategies interactions Jürgen Bolz, Jena Kerry Tucker, Basel Wiring Molecules for the Assembly of Cortical A green mouse: Using GFP to study peripheral Circuits nervous system development Heiko Braak, Frankfurt Michael Wegner, Erlangen Neuropathological staging of idiopathic Sox10 Function in PNS and CNS Development Parkinson's disease and some speculative Michael Weller, Tübingen considerations pertaining to its pathogenesis Biological relevance and therapeutic modulation of Christian Brösamle, Baltimore cytokine activty (Apo2L/TRAIL, TGF-ß) in Myelination in the vertebrate brain – more than malignant glioma axonal insulation Nils Brose, Göttingen Dynamic Regulation of Active Zone Function in Neurotransmitter Release 99 Symposia and Seminars

Graduate College 791 Seminars of the DFG ’Forschergruppe’ FOR “Neural Development and Degenerative 302/2-1, 2001 Processes: Basic Research and Clinical Implications” Michael Aggensteiner, Leipzig Klonierung und Quantifizierung der entwicklungs- abhängigen Genexpression von p42IP4 im Winter Term 2002/2003 Rattenhirn

Karsten Thelen /G.E. Pollerberg Eva Grundström, Uppsala Neuronal migration and axonal pathfinding On Pathophysiological Mechanisms in Amyotrophic Lateral Sclerosis Christof Niehrs Molecular mechanisms of early antero-posterior Brigitte Kieffer, Illkirch patterning Opioid receptors: from genes to mice Rainer Friedrich Reinhard Müller, Leipzig Organization and development of the peripheral Untersuchungen zur 6-Phosphofrukto-1-kinase in olfactory system humanen Fibrolasten Hannah Monyer Beate Niesler, Heidelberg Elektrische und exzitatorische Synapse während der Genetic variability of the human serotonin receptor Entwicklung HTR3 genes and cloning of alternatively spliced isoforms Harald Hutter Axon guidance signals: Molecules and Mechanisms Flora de Pablo, Madrid Antiapoptotic signalling of the insulin/insulin Veit Witzemann receptor system in early neural development Formation of synapses at the neuromuscular junction - a change of the neurocentric view John Peters, Dundee Physiology and Pharmacology of Native and Dirk Feldmeyer Recombinant 5-HT3 Receptors Neuronal networks in the neocortex – structural and functional properties Dmitry Poteryaev, Helsinki The role of GDNF family receptors alpha in Ret- Klaus Unsicker mediated oncogenesis and neuronal function Development of the nervous system and related malformations Enrique de la Rosa, Madrid Programmed cell death during early neural development: its physiological regulation by intrinsic and extrinsic signals Norman Saunders, Tasmania, Australia Barriers in the developing brain, control of its internal environment Katharina Schindowski, Frankfurt Mechanismen der apoptotischen Zelltodes an peripheren Zellen in der Alzheimer Demenz

100 Symposia and Seminars

Seminar Developmental Neurobiology, Yong-Boum Kim Summer Term 2001 Specifying neuronal identity by combinatorial RNA splicing Tobias Wolfram Jan-Marik Weislogel Turning Blood into brain Isolation of neural stem cells in the mammalian CNS Christine Jakoby Christina Bauch Neuralrohrsegmentierung Festlegung der Neuralrohrachsen während der Esther Zanin Embryogenese The control of neuronal cell shape Simone Giese Neurobiology Seminars 2002 Die Entstehung einer Synapse: Differenzierung von Synapsen im ZNS John Creemers, Department for Human Genetics, Leuven Intracellular Trafficking and Pathophysiology of Susanne Fritsch Proprotein Convertases The formation of neuromuscular synapses Oliver Dick, MPI für Hirnforschung, Frankfurt Ida Kollmar Localization and function of cytomatrix-proteins at How developing neurons balance their economies retinal synapses Florian Stindl Thomas Dresbach, Leibnitz-Institut für Neurobiologie in Signal-processing machines at the postsynaptic Magdeburg density. Golgi-derived precursor organelles in assembly of Sandra Dischinger neurotransmitter release sites Die Enstehung einer Synapse II: Präsynaptische Lara Gnügge, University Freiburg, Department of Developmental Differenzierung Biology Vanessa Schubert The making of GFP transgenic zebrafish for Neuronenwanderung während der ZNS- pancreas tracking and mutant characterization Entwicklung Javeed Jiqbal, Hans-Knöll-Institute For Natural Products Yasmin Issa Research, Department of Cell and Molecular Die Entstehung einer Synapse III: Postsynaptische Biology, Jena Differenzierung Genotyping and Gene expression profiling in HPV 16 immortilized cell lines with cDNA microarrays Winter Term 2002/03

Isabel Brachmann Oligodendroglial development Holger Baldauf Retino-tectal projection Lothar Blüm Entwicklung des Geruchssinns Andreas Wippel Ta ngentiale Zellwanderung im zentralen Nervensystem

101 Symposia and Seminars Symposia

SFB 488 Christmas Symposium 2001 - Saturday, SFB 488 Christmas Symposium 2002 - Saturday, 01.12.2001, ZMBH 30.11.2002, ZMBH Session 1: Neural Induction, pattern formation, and cell Session 1: determination Chair: H. Bading (Chair: G. E. Pollerberg) A1 C. Niehrs A Wnt morphogen gradient controls antero- Christof Niehrs Role of dkk1 in embryonic head induction posterior patterning of the early neural Judith Stegmüller / Identification of intracellular binding partners plate in Xenopus Jacqueline Trotter of the AN2/NG2 proteoglycan. A6 K. Unsicker TGFßs as master regulators of neuron Klaus Unsicker Development of sympathoadrenal progenitor survival and death cells and their preganglionic innervation B5 S. Offermanns Mechanisms of RhoA activation in neuronal Session 2: Axon growth and pathfinding and non-neuronal cells (Chair: Christof Niehrs) B6 R. Kuner Molecular mechanisms governing Roland Brandt Cytoskeletal mechanisms of neuronal nociceptive transmission at spinal synapses morphogenesis Session 2: Hans-Hermann Membrane traffic in neuronal cell systems Chair: H. Monyer Gerdes J. Kuhse Developmental expression and localization Stefan Offermanns Mechanisms of Rho regulation in neuronal of NMDA-receptor subunits in primary cells cultures of rat spinal cord neurons: effects of agonist and antagonist administration Dusan Bartsch Conditional overexpression of the minibrain kinase in mouse brain B2 H.-H. Gerdes Dendritic membrane traffic Session 3: Neuronal differentiation D8 W. Wisden Developing a transgenic method to regulate (Chair: Klaus Unsicker) reversibly the activity of specific neuronal types Gunter Merdes / Notching up APP in Drosophila Renato Paro D9 U. Misgeld D1 tone modulates synaptic inhibition in substantia nigra Peter Seeburg Genetic approaches to understand GnRA pulsatility in hypothalamic GnRA neurons Session 3: Chair: J. Kirsch Session 4: Molecular bases of synapse formation (Chair: Hannah Monyer) B4 K. Thelen Role of NrCAM and DM-GRASP in guidance of retinal ganglion cell axons Hannah Monyer Functional importance of gap-junction coupling in the postnatal brain Th. Euler Direction-selective calcium signals in retinal starburst amacrine cells Ulrich Misgeld The developmental switch of neuronal GABAergic responses from excitation to D6 T. Lemberger Brain-specific CREB mutants and inhibition neurodegeneration Veit Witzemann Factors required for AChR clustering at the D3 H. Monyer To mnemonists in the literature of the 20th neuromuscular junction century Daniel Gau / Phosphorylation of CREB Ser-142 regulates Günther Schütz light-induced phase shifts of the circadian clock

102 Symposia and Seminars

SFB 488 Symposium SFB 488 Symposium „Neural and Non-Neural Stem Cells“ ’Frontiers in Developmental Neuroscience‘ Heidelberg, October 26./27., 2001 Heidelberg, June 14./15, 2002 Friday, Oct 26, 2001 Friday, June 14 Session 1 - Chair: Klaus Unsicker Session 1: Induction and patterning I - Chair: Klaus Unsicker Oliver Brüstle Embryonic stem cells: Applications in Yoshiki Sasai, Kyoto Molecular control of neural specification in frog reconstructive neurobiology and mouse ectoderm Anna Wobus Embryonic stem cell differentiation: Modulation Christof Niehrs, Molecular mechanism of embryonic head induction by genetic modification and extracellular signals Heidelberg by Dickkopf1 Gerd Kempermann Genetic and functional aspects of adult Wolfgang Wurst, Mid-/Hindbrain development: From embryonic to neurogenesis München adult physiology Key Note Lecture Session 2: Patterning II and determination - Chair: Christof Niehrs Helen M. Blau The evolving concept of a stem cell: entity or David Wilkinson, Regulation of cell migration by Eph receptors and function? London ephrins Saturday, Oct 27, 2001 Arnon Rosenthal, Control of monoaminergic neuronal cell fate in the Session 2 - Chair: Roland Brandt Palo Alto vertebrate brain Margot Mayer-Pröschel Gliogenesis in the mammalian spinal cord: from Renato Paro, Notching up the Amyloid Precursor Protein (APP) the embryo to the adult Heidelberg in Drosophila Magdalena Götz Glial cells generate neurons: cellular and François Guillemot, Common and divergent functions of proneural molecular mechanisms of neurogenesis in the vertebrate CNS Illkirch genes in specification of neural cell types Clive N. Svendsen Human neural precursor cells grown as Saturday, June 15, 2002 neurospheres are regionally specified Session 3: Visual system and neural crest – Chair: Renato Paro Session 3 - Chair: Horst Simon Matthias Carl, Genetic and molecular analysis of vertebrate eye Heidelberg development Angela Gritti Neural stem cells in the adult brain: the SVZ-RMS Chaya Kalcheim, Cell intrinsic and environmental factors regulating pathway Jerusalem the onset of neural crest migration Rudolf Götz Signalling pathways for survival and Jean-François Brunet, Phox2b, master gene of a neural circuit differentiation of neural cells Paris Karen J. Chandross Adult mammalian bone marrow gives rise to Hermann Rohrer, Molecular control of noradrenergic neuron neural-like cells in the brain Frankfurt/Main development Georg Kuhn Neural stem cell activity in the adult brain: The balance of proliferation and apoptosis Carmen Birchmeier, The role of the Neuregulin signaling system in Session 4 - Chair: Peter Seeburg Berlin development of the peripheral nervous system Session 4: Migration, synapse formation and glia – Chair: Chaya Kalcheim Anthony D. Ho Non-hematopoietic tissues from hematopoietic Michael Frotscher, How does reelin control granule cell migration in stem cells? Freiburg the dentate gyrus? Albrecht Müller Developmental potentials of somatic stem cells: Eduardo Soriano, Mechanisms of Reelin action in cortical unique or all the same? Barcelona development Wolfgang M. Franz Selection of ventricular-like cardiomyocytes from Christian Klämbt, Glial cell migration in Drosophila ES cells in vitro Münster Session 5: Formation of networks and plasticity – Chair: Peter Seeburg Matthew Dalva, A role for EphB in synapse development: regulating Boston NMDA receptor localization and function Hilmar Bading, Dynamics of simple neuronal networks Heidelberg Klaus Willecke, Bonn Analysis of glial and neuronal connexins in transgenic mouse mutants Hannah Monyer, Functional role of GAP junction coupling in the Heidelberg developing and the adult brain

103 Symposia and Seminars

IZN Retreat St. Odile, Alsace Session VI (3 talks): from molecules to systems (4) Chair: Harald Hutter April 5 - April 7, 2001 William Wisden Homeostatic regulation of gene expression in Thursday, April 5, 2001 the developing brain Introduction: Klaus Unsicker: Neuro-Development in Heidelberg Anne Régnier- Anti-tumour immunity in the brain: Session I: From molecules to cells (1) Chair: Hannah Monyer Vigouroux an impossible talk? Jan Rohde Assembly and function of integral membrane Brigitte Wildemann The diagnostic and pathogenetic (Langosch group) proteins implications of lymphocytic gene Hans-Hermann Membrane traffic in neuronal cell systems rearrangements in malignant lymphomas of Gerdes the nervous system and multiple sclerosis Evi Albers From cell migration to membrane traffic: Discussion: Neurophilosophy - Future of Heidelberg Neuroscience (Trotter group) current topics in myelin biology Hilmar Bading Session II: From molecules to cells (2) Chair: Peter Seeburg Saturday, April 7, 2001 Session VII (3 talks): from molecules to systems to cognition Uwe Ernsberger To build a neuron Chair: Klaus Unsicker Hannah Monyer GABAergic interneurons: their role in Heinz Steffens The Na+-channel blocker tetrodotoxin: rhythmicity and synchronicity of neuronal (Mense group) a tool in systemic networks neuroscience research? Herta Flor Cortical plasticity: mechanisms and Ulrich Misgeld Regulation of chloride transport in neurons functional significance Friday, April 6, 2001 Roland Brandt From tubules to cognition Session III (2 talks): From molecules to systems (1) Chair: Ulrich Misgeld Peter Seeburg RNA editing in mammals: developmental deficiencies revealed by genetic interference Dirk Feldmeyer Excitatory neurotransmission in the neocortex Session IV (2 talks): Fom molecules to systems (2) Chair: Roland Brandt Klaus Unsicker Autonomic motoneurons in the spinal cord: how similar to, how different from somatic motoneurons? Horst Simon Specification of the midbrain dopaminergic neurons Session V (3 talks): From molecules to systems (3) Chair: Hans- Hermann Gerdes Harald Hutter Axon guidance genes in C. elegans: help from the genome sequence Erich Greiner Genetic dissection of tailless function in developing and adult mouse brain Jochen Wittbrodt From eye to brain: optic vesicle morphogenesis, retinal patterning and projection

104 Symposia and Seminars

IZN Retreat Horst Simon Differentiation of the midbrain dopaminergic Kloster Schöntal, May 7 – 8, 2002 neurons Neurosciences at the IZN: Where to go Session 5 Chair: J. Trotter Concepts and Techniques Markus Molecular and genomic approaches in stroke Schwaninger research Rainer Spanagel Neurobiological bases of drug addiction Siegfried Mense Plans and ideas for studying mechanisms of Tuesday, May 7 muscle pain in vivo Session 1 Session 6 Chair: H. Monyer Chair: H. Hutter Klaus Unsicker IZN: Past, Presence, and Future Directions Christoph Cremer Lightoptical Nanoscopy Hilmar Bading From molecules to networks: my concepts Philippe Bastiaens Imaging RTK signal initiation, propagation Klaus Unsicker From systems to molecules: a top-to-bottom and termination in cells approach Francesca Ciccolini A new strategy for isolating neural stem cells Ad Aertsen From Neurons to Networks and Back -- Uwe Ernsberger To build a neuron - conceptually Recurrent Approaches in Neural Dynamics Session 7 Session 2 Chair: G. E. Pollerberg Chair: K. Unsicker O. von Bohlen und NO visualization Joachim Kirsch Forming inhibitory synapses Halbach Peter Vogel Antiapoptotic interventions and outcome Andreas Draguhn Analysis of high-frequency network following global cerebral ischemia due to oscillations in the rodent hippocampus in cardiocirculatory arrest vitro Wolfgang Kelsch Characterization of KCC2 by its cation Session 3 dependence Chair: H. Bading Peter Vanhoutte NMDA receptor-induced unsilencing of Jörg Hoheisel Analysis of Genetic Variations in Cancer synaptic contacts triggers change in neuronal Tissue by Complex DNA and Antibody network properties Microarrays Winfried Denk Multiphoton imaging in neurosciences

Rainer Friedrich Network dynamics and odor processing in the olfactory bulb Special Lecture - Peter Ruppersberg Venture capital and biotech companies in the crisis Wednesday, May 8: Session 4 Chair: U. Misgeld Hannah Monyer From molecules to networks to mind: my concepts Bill Wisden Selective neuronal silencing: a review of possible approaches

105 Symposia and Seminars

Graduate Workshop: Live Cell Imaging Chris Hawes Expression of fluorescent proteins in plant cells for September 24-30, 2001 the study of organelle dynamics Jennifer Lippincott-Schwartz GFP-based multi-color imaging - automated Dissection of intracellular protein trafficking quantitative image analysis - microinjection pathways using FRAP and FLIP Rainer Pepperkok Using GFP to study structure and function in the Organizers: secretory pathway Tullio Pozzan • Hans-Hermann Gerdes (Heidelberg) Imaging second messengers in living cells • Brian Storrie (Blacksburg) Ernst Stelzer The truth behind confocal microscopy Brian Storrie Instructors: Imaging Golgi apparatus biogenesis through expression of dominant mutations • Ta nja Kögel

• Amin Rustom

• Rüdiger Rudolf

External speakers Vicky Allan Using transmitted light microscopy to study organelle movement in vivo and in vitro Philipp Bastiaens Spatial organisation of tyrosine kinase and phosphatase activities Jan de Mey Living cells in depth: analysing cellular processes by ultrafast 4D recording of two fluorescent tagged proteins and high troughput deconvolution Hans-Hermann Gerdes The use of GFP to monitor protein secretion Roland Eils 4D imaging reveals new insights into cellular and nuclear dynamics Jan Ellenberg 4D imaging and fluorescence photobleaching to study nuclear envelope structure and function in live cells. 106 Symposia and Seminars

ZMBH Forum 2001 Bart De Strooper (Leuven) The secretases as drug targets in the fight against "Genes, Proteins and Brain Disease" Alzheimer's Disease Martin Citron (Thousand Oaks) Heidelberg, May 17 to 19, 2001 ß-secretase - a target for the treatment of Alzheimer's Disease Ronald K. Taylor (Hanover) Thursday, 17.05.2001 Characterization of a novel family of polytopic aspartyl proteases that contribute in diverse ways Keynote Lecture: to the pathogenesis of human disease Colin L. Masters (Melbourne) Wieland Huttner (Dresden) Amyloid proteins in neurodegenerative diseases: 17 Neurogenesis and the cell biology of years from Sequenator to clinic neuroepithelial cells

Friday, 18.05.2001 Saturday, 19.05.2001 Session I (Chair: Tobias Hartmann) Session III (Chair: Klaus-Armin Nave) Adriano Aguzzi (Zuerich) Steven Younkin (Jacksonville) Molecular Biology of Prion Diseases Plasma A beta as a premorbid biomarker and Christian Haass (Munich) surrogate phenotype for typical late onset Amyloid ß-Peptide and Synuclein, two major Alzheimer's Disease players in Neurodegeneration Lars Lannfelt (Huddinge) Ta Yuan Chang (Hanover) Genetics and pathophysiology of Alzheimer's Cholesterol Mutants at Dartmouth disease Hilkka Soininen (Kuopio) Risk genes of Alzheimer's disease – approach of Session VI (Chair: Klaus Unsicker) genome wide search Tobias Hartmann (Heidelberg) Rudolph E. Tanzi (Charlestown) The role of lipids in Alzheimer Amyloid Precursor Alzheimer's Disease: Resolving a Complex Genetic processing Picture Thomas Bayer (Bonn) Michel Goedert (Cambridge) What can we learn from transgenic mice to Tau gene mutations and neurodegeneration understand the pathology of Alzheimer´s disease? Thomas Jentsch (Hamburg) Session II (Chair: Gerd Multhaup) Role of intracellular C1--channels - lessons from mouse models and human disease Peter St. George-Hyslop (Toronto) Biology and Genetics of the Presenilins and of their Partners Sangram S. Sisodia (Chicago) Function and Dysfunction of Presenilin 1

107 Symposia and Seminars Workshop on Molecular Cell Biology to Nucleus Blanche Schwappach The Hebrew University of Jerusalem and Quality control in the heteromultimeric assembly of The University of Heidelberg ion channels and receptors May 8 – May 12, 2002 Thomas Lemberger Disruption of CREB function in brain leads to ZMBH, INF 282, SR 001 progressive neurodegeneration Nissim Ben Arie Math 1 in neurogenesis Thursday, May 9 Gudrun Rappold Session I: Genes and Development Functional disruption of a Rho-GTPase activating gene on chromosome 3p25 causes severe mental Klaus Unsicker retardation Generation of neural crest-derived neuroendocrine Ulrich Misgeld cells and their integration into a neural circuitry Developmental change of GABA response and Uri Gat chloride transport in neurons The Wnt pathway in the development of hair and Session IV: Molecular and Physiological Aspects of other skin appendages Nervous System Function Hermona Soreq Session II: Transcriptional and Subcellular Signalling The molecular neurobiology of acetylcholinesterase variants: from stressful insults to antisense Christof Niehrs intervention Molecular mechanism of embryonic head induction by dickkopf1 Hannah Monyer Molecular determinants for oscillatory and Avihu Klar synchronous network activity Plasmin modulates the axonal guidance properties of F-spondin Yifat Prut Neuronal networks: from structure to function Roland Brandt Mechanisms of neuronal degeneration in the tau Yael Stern-Bach pathologies Neuronal functioning of glutamate ion channels Oded Behar Israel Steiner The role and mechanism of action of Semaphorin Herpes simplex virus type I (HSV-1) latency: the 3A in axon guidance many functions of the HSV-1 latency associated gene Renato Paro Chromatin and Epigenetics Saturday, May 11 Zeiev Paroush Session IV: Molecular and Physiological Aspects of Tra n scriptional repression in Drosophila Nervous System Function, cont`d development Guy Bloch Peter Seeburg Per gene expression in the honey bee Synaptic activity-induced conversion of intronic to exonic sequences Michael Brandeis Cell cycle-associated genes Rainer Spanagel Friday, May 10 The role of per genes in drug addiction Session III: Transduction Processes from Membrane

108 Guest Scientists

Theses Guest Scientists 2001-2002 Guest Scientists 2001-2002

• Nicole Dünker. PhD, Neuroanatomy, Universität Göttingen, Group Hilmar Bading, Neurobiology Göttingen, Germany (09/02)

• Anke Lackmann, PhD, Neuroanatomy, Universität Göttingen, • Giles Hardingham, Department of Preclinical Veterinary Studies, Royal School of Veterinary Studies, Edinburgh Göttingen, Germany (12/02) University- Summerhall, Edinburgh, England (02/02 - 09/02, • Beata Legutko, PhD, Pharmacology, Polish Academy of part-time) Sciences, Krakow, Poland (07/02)

• Azita Parvaneh Tafreshi, PhD, Research Centre for Genetic Group Roland Brandt, Neurobiology Engeneering and Biotechnology, University of Teheran, Teheran, Iran (07/01 – 06/02) • Pavol Zelina, Slovak Academy of Sciences, Bratislava, Slovakia • Dmitry Poteryaev, PhD, Institute of Biotechnology, University of (07/01 – 08/01) Helsinki, Helsinki, Finland (12/01 – 05/02)

• Elena Roussa, PhD, Neuroanatomy, Universität Göttingen, Group Uwe Ernsberger, Neuroanatomy Göttingen, Germany (04/02)

• Ulla Amtmann, Clinical Neurobiology, Neurology, University Heidelberg (05/01)

• L. Paraoanu, Biology, Techn. Univ. Darmstadt (06-07/01)

• N. Dünker, Anatomy, University Homburg, Homburg(10/01)

Group Hans-Hermann Gerdes, Neurobiology

• Dr. Ivanka Markovic, School of Medicine, Institute of Biochemistry, Belgrad (08-10/02)

Group Siegfried Mense, Neuroanatomy

• Prof. D.G. Simons, MD, Physical Med. & Rehabilitation, Emory University, Atlanta, Ga, USA (05/01, 09/02)

Group Hannah Monyer, Clinical Neurobiology

• Prof. Dr. Roberto Bruzzone, Institut Pasteur, Paris (06/02 - 2 years)

Group Klaus Unsicker, Neuroanatomy

• Urmas Arumäe, PhD, Institute of Biotechnology, University of Helsinki, Helsinki, Finland (10/02)

• Cesar Berrios, Dept. Biology, University of Puerto Rico, San Juan, Puerto Rico (03-06/02)

110 Diploma and Doctoral Theses Diploma and Doctoral Theses 2. Doctoral Theses

1. Diploma Theses Group Roland Brandt, Neurobiology

Group Roland Brandt, Neurobiology Jochen Eidenmüller (2001) Simulierung einer Alzheimer'schen Erkrankung Julia Leschik (2000) ähnlichen Hyperphosphorylierung des Expression von GFP-markiertem Tau-Protein und mikrotubuliassoziierten Proteins Tau. PHF-ähnlichen Tau-Phosphomutanten in Thomas Fath (2002) Hippocampus-Schnittkulturen Die Rolle des Mikrotubuli-assoziierten Proteins Tau Zsófia Sebö (2001) in neurodegenerativen Erkrankungen Funktionale Analyse einer Tau-Mutanten (R406W), Jörg Piontek (2002) die in der neurodegenerativen Krankheit FTDP-17 Herstellung monoklonaler Antikörper gegen auftritt Proteine des neuronalen Membrankortex und Carlos Bas Orth (2002) Untersuchung von Gravin-Signalkomplexen in Analyse der Funktion des Kinase verankernden humanen Modell-Neuronen. Proteins Gravin in Nervenzellen Sonja Grosskinsky (2002) Group Hans-Hermann Gerdes, Neurobiology Charakterisierung neuer "Alzheimer-diagnostischer Antikörper" und Antikörper gegen weitere Rüdiger Rudolf (2001) neuronale Zytoskelett-Antigene Bildung. Transport und Exozytose sekretorischer Granula und die funktionelle Beteiligung von Myosin Va Group Hans-Hermann Gerdes, Neurobiology Thorsten Salm (2001) Oliver Schlicker (2001) Maturierungsabhängige Assoziation von Myosin Va Untersuchung zum Transport von GABA-A-alpha1 mit sekretorischen Granula und alpha2 GFP-Fusionsproteinen Group Siegfried Mense, Neuroanatomy Group Jacqueline Trotter, Neurobiology Thomas Blüm (2001) Christine Neuber (2003) Fibroblasten Wachstumsfaktor-2 moduliert die Vesikeltransport und Sortierung von Proteinen und Impulsaktivität spinaler Neurone Lipiden in myelinisierenden Oligodendrozyten Christine Winterstein (2003) Group Hannah Monyer, Clinical Neurobiology Mögliche Interaktionspartner der AN2/NG2- positiven Zellen, vermittelt über die LNS-Domänen Elke C. Fuchs (2002) Generierung transgener Mauslinien zur Untersuchung der AMPA-Rezeptor-Funktionen in Group Horst Simon, Neuroanatomy GABAergen Interneuronen. Christian Scholz (2002) Die Entwicklung der dopaminergen Neurone im Mittelhirn des Huhns

111 Diploma and Doctoral Theses

Group Horst Simon, Neuroanatomy

Sandrine Thuret (2002) Identification and Characterization of Genes Expressed by the Midbrain Dopaminergic Neurons

Group Jacqueline Trotter, Neurobiology

Brigitte Schauwienold (2001) Klonierung und Charakterisierung von BS1, einem Mitglied der RUN-Familie Corinna Klein (2001) Signaltransduktion zum Zytoskelett in Oligodendrozyten während der Myelinisierung Judith Stegmüller (2002) Molekulare Analyse des Proteoglykans NG2/AN2 und Identifizierung von seinen intrazellulären Bindungspartnern in glialen Zellen

Group Klaus Unsicker, Neuroanatomy

Heike Specht (2001) Subzelluläre Lokalisation und Mechanismen der Sekretion von transformierenden Wachstumsfaktoren ß in neuronalen Zellen

112

2EPORT�  Table of Contents

2EPORT� Table of Contents