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Pdf Poster Session PSM06 Metabolism Journal of Neurochemistry, 94 (Suppl. 1), 1–51 Plenary Talk P01: Experience-dependent modification of neural circuits – cellular and molecular mechanisms Mu Ming Poo Division of Neurobiology, Department of Molecular & Cell Biology, Berkeley, CA, USA Correlated spiking of pre- and postsynaptic neurons can result persistent potentiation and depression of specific retinotectal in strengthening or weakening of glutamatergic and GABAer- and intratectal synapses. Interestingly, activity-induced synaptic gic synapses, depending on the order of and/or the time inter- modifications in vivo are quickly reversed by either subsequent val between the pre- and postsynaptic spiking. The functional spontaneous activity in the tectum or exposure to random visual significance of this synaptic modification is illustrated by the inputs. Such reversal depends on the activation of the NMDA experience-dependent development of Xenopus retinotectal subtype of glutamate receptors and postsynaptic protein phos- system. Activity-induced modification of retinotectal synapses photases. However, stabilization of synaptic modifications can underlies the refinement of the receptive field of tectal neurons, a be achieved by an appropriately spaced pattern of visual stimuli. process involving a progressive matching of excitatory (retino- Taken together, these findings underscore the importance of tectal) and inhibitory (intratectal) inputs to the tectal neuron. spike timing-dependent synaptic plasticity and suggest a tem- Furthermore, the receptive field properties can also be rapidly poral constraint on the pattern of sensory inputs for effective ‘trained’ by conditioning visual stimuli through a selective and modification of developing neural circuits. © 2005 International Society for Neurochemistry 2 Symposium S01 Symposium S01: Molecules and mechanisms in Schwann cell development Chair: K.R. Jessen & R. Mirsky S01-01 S01-03 The function of Notch and stress kinase Purinergic signaling molecules regulating signals in early Schwann cell development schwann cell development in response to KR JESSEN, R MIRSKY, A WOODHOO, D PARKINSON and impulse activity in axons A BHASKARAN RD FIELDS Department of Anatomy and Developmental Biology, University National Institutes of Health, NICHD, Bethesda, MD, USA College London, London, UK Development of myelinating glia is regulated by a complex variety of Embryonic Schwann cell development involves two main transitions: interactive and dynamically regulated signals from developing axons, (1) the emergence of Schwann cell precursors (SCPs) from neural crest including neural impulses. Impulse activity is detected by premyeli- cells, (2) the generation of immature Schwann cells from SCPs. The nating glia in part by the activity-dependent release of ATP from axons, third major transition in the lineage is the largely postnatal diversifi- which is hydrolyzed by ectonucleotidases to ADP, AMP, and adeno- cation of immature Schwann cells to form myelinating and non- sine. These extracellular signaling molecules activate different puriner- myelinating Schwann cells. This talk will focus on the function of gic receptors on Schwann cells regulating various second messengers Notch signalling in controlling the SCP/Schwann cell transition, pro- and protein kinases, including cAMP and Ca2+, erk 1/2 and p38 MAPK. liferation of immature Schwann cells and the onset of myelination. The In comparison with growth factors, the developmental effects of function of Notch and stresskinase singalling,in particular the JNK/ purinergic signaling on Schwann cell development have received c-Jun pathway, as negative regulators of myelination will be discussed, much less attention. Our laboratory is exploring how these activity- as well as the interactions between these pathways and the pro-myelin dependent purinergic signaling molecules function in concert with transcription factor Krox-20. other axonal signals to regulate proliferation and development of Schwann cells. The results indicate that the effects of impulse activity, growth factors, and purinergic receptor activation are context-dependent. Opposite effects of adenosine on SC proliferation and erk/MAPK acti- S01-02 vation are seen in the presence and absence of growth factors, for Krox-20/Egr2 collaborators and regulation of example. This suggests that the biological effects of impulse activity gene expression during myelination of the and growth factors are dependent upon the complement of different peripheral nervous system signals impinging upon the cell at any given time. These considerations may help explain how axonal signals can have different biological J SVAREN*, SE LEBLANC*, R SRINIVASAN*, C FERRI†, effects at different stages of development. GM MAGER*, AL GILLIAN-DANIEL* and L WRABETZ† *University of Wisconsin, Madison, WI, USA, †San Raffaele Scientific Institute, DIBIT, Milan, Italy Myelination of peripheral nerves by Schwann cells is coordinated by transcriptional regulatory proteins that trigger various genetic events in the synthesis and compaction of myelin. One central aspect of myelin formation is the requirement for a large amount of lipid and cholesterol biosynthesis, and recent experiments have suggested that Egr2/Krox-20 may trigger induction of cholesterol and lipid biosyn- thetic enzymes at the transcriptional level. To elucidate the control of cholesterol and lipid biosynthetic genes during peripheral nerve myeli- nation, we investigated how expression of the Sterol Regulatory Element Binding Protein (SREBP) pathway components is affected by the absence of Egr2. During myelination of sciatic nerve, there is a very significant induction of SREBP1 and SREBP2, as well as their target genes, suggesting that the SREBP transactivators are important regulators in the myelination process. In addition, the expression levels of lipid/cholesterol biosynthetic genes are dramatically reduced in sciatic nerves from mice with a targeted disruption of Egr2, and we found that Egr2 and SREBP2 can coordinately activate expression of several SREBP target genes, including HMG CoA reductase. In summary, our data indicate that Egr2/Krox-20 interacts with SREBP activators to directly regulate cholesterol/lipid biosynthetic genes as part of the myelination program. © 2005 International Society for Neurochemistry, Journal of Neurochemistry, 94 (Suppl. 1), 1–51 Symposium S01 3 S01-04 Tyrosine kinase signaling in peripheral nerve tumorigenesis N RATNER, KR MONK, J WILLIMAS, B LING, S MILLER and J WU Dept. Pediatrics, Cincinnati Children’s Hospital, University of Cincinnati, Cincinnati, OH, USA Benign peripheral nerve tumors called neurofibromas are a major source of morbidity for patients with the inherited disease neurofibro- matosis type 1 (NF1). We developed a tissue culture model of periph- eral nerve tumorigenesis in NF1. NF1-/-TXF Schwann cells have loss of function mutations at NF1, and, like Schwann cells in neurofibro- mas, lose contact with axons and aberrantly express the epidermal growth factor receptor (EGFR). When the human EGFR is expressed in Schwann cells (CNPase-hEGFR mice), a neurofibroma-like pheno- type develops (Ling et al. Cancer Cell 2005; 7: 65–75). CNPase- hEGFR mice also show hypoalgesia, consistent with disruption of neuron-glial interaction we described in CNPase-hEGFR mouse nerves. We used the CNPase-hEGFR mouse model to test response to the EGFR antagonist Cetuximab (ImClone Systems). We administered Cetuximab at various times beginning at birth. Nerve hypertrophy, mast cell accumulation, collagen deposition and disrupted axon-glial inter- actions characteristic of this model were all normal at three months of age only when mice were treated early in life. The results suggest that application of anti-EGFR therapeutics in young animals blocks tumori- genesis by halting a crucial step (perhaps Schwann cell proliferation) in a cascade of events that leads to complex changes characteristic of neurofibroma formation. Acknowledgement: Supported by NIH-NS28840 and DAMD-17-02- 1-0679. © 2005 International Society for Neurochemistry, Journal of Neurochemistry, 94 (Suppl. 1), 1–51 4 Symposium S02 Symposium S02: Progress on the pathogenesis of hereditary neurodegenerative disorders Chair: L. Notterpek S02-01 we have generated a transgenic mouse model that over-express mutant Presenilins in the pathogenesis of Alzheimer’s APP (swe/ind) from a vector that can be regulated by doxycycline. disease Under induced conditions, high level expression of APPswe/ind quickly leads to fulminant amyloid pathology. We show that adminis- G THINAKARAN tration of doxycycline inhibits transgenic APP expression by 95% and The University of Chicago, Chicago, IL, USA abruptly halts the progression of amyloid pathology. However, exist- Sequential processing of amyloid precursor protein (APP) by b- and g- ing amyloid plaques require a far longer interval to disperse than to secretases releases the 39–42 amino acid long beta-amyloid (Ab) pep- assemble and associated pathologies likewise persist. Our findings tides, which accumulate in the brains of aged individuals and patients suggest that arresting A-beta production in AD patients should halt the with Alzheimer’s disease (AD). The major b-secretase is an aspartyl pro- progression of pathology, but that early treatment may be imperative tease termed BACE-1, which cleaves APP within the ectodomain. Ab is as repair of amyloid induced damage appears to be a very slow process. then released by intramembraneous cleavage by g-secretase, a multipro- tein complex made of four
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