DkYb[_Y7Y_ZiWdZCeb[YkbWh8_ebe]o 23 I[h_[i;Z_jeh >$@$=heii Institut für Biochemie Biozentrum Am Hubland 97074 Würzburg Germany Dieter B. Wildenauer (Ed.) Molecular Biology of Neuropsychiatric Disorders With 15 Figures and 8 Tables Editor Dieter B. Wildenauer Graylands Hospital Center for Clinical Research in Neuropsychiatry (CCRN) Claremont WA 6910 Australia ISBN 978-3-540-85382-4 e-ISBN 978-3-540-85383-1 ISSN 0933-1891 Library of Congress Control Number: 2008933566 © 2009 Springer-Verlag Berlin Heidelberg This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Cover design: Boekhorst Design BV, The Netherlands Printed on acid-free paper 9 8 7 6 5 4 3 2 1 springer.com Preface The intention of this book is to give an overview about ongoing research into molecular causes for disorders that affect the human brain. These disorders afflict mainly human behavior and are, since borders between “normal” and “abnormal” behaviors are continuous and hard to define, not always easy to diagnose. We have included the major psychoses (schizophrenia and affective disorders), autism, attention deficit hyperactivity, and anxiety disorders, as well as addictive and suicidal behavior. Neuropathological alterations in these disorders are usually not detectable or restricted to sporadic cases and, if present, not easy to define as causative. In contrast, patho- logical alterations in the brain are present in the two included neuropsychiatric disor- ders, Alzheimer’s and Parkinson’s disease. Detection of pathological abnormalities has been helpful as a starting point for studies of the biochemistry and molecular biology of these diseases. Our goal was to describe current research directions using new methods and information provided by molecular biology and molecular genetics. We have included selected, but in our opinion (and therefore biased) most promising, findings rather than attempting to give a complete overview of findings in these disorders. Given the large number of publications appearing each month in the field (up to 50 in one month as estimated from the PubMed entry) it is almost certain that the book would be already out of date while still in print. Specific databases that col- lect all new information on websites accessible to the public are superior and already available for schizophrenia (http://www.schizophreniaforum.org/res/sczgene/default. asp), Alzheimer’s disease (http://www.alzforum.org/res/com/gen/alzgene/default. asp), and Parkinson’s disease (http://www.pdgene.org/). The complex nature of psychiatric disorders with many factors contributing to susceptibility, but not always necessary for expression of the disease, renders the identification of molecular causes extremely difficult. Whilst causes for the two neurodegenerative disorders, Alzheimer’s and Parkinson’s disease, have been uncovered and their molecular biology is being studied, the search for causes for other neuropsychiatric disorders has not yet led to convincing findings. Complexity and variation in phenotype are major obstacles for these studies. In particular, the difficulty of phenotype definition makes it is hard to establish identical samples for replication or confirmation of findings. As a consequence, most of the published findings are not easy to prove or disprove and may just add to the flood of unconfirmed positive findings in the field. Nevertheless, we are optimistic that a continuing collection v vi Preface of data will be of help in the discovery of the molecular connections and pathways that play a critical role in the development of these disorders. Finally, I wish to thank all contributors to this book, as well as Professor Dr. Hans J. Gross for encouragement and Frau Gramm from Springer Verlag for help in submission for publication. Perth Dieter B. Wildenauer June 2008 Contents Decoding the Genetics and Underlying Mechanisms of Mood Disorders ............................................................................................ 1 Sevilla D. Detera-Wadleigh and Takeo Yoshikawa 1 Introduction .................................................................................................... 2 2 Bipolar Disorder ............................................................................................. 5 2.1 Clinical Presentation and Epidemiology .............................................. 5 2.2 Genetic Analysis ................................................................................... 6 2.3 Alternative and Complementary Strategies .......................................... 15 3 Depression ...................................................................................................... 24 3.1 Clinical Presentation and Epidemiology .............................................. 24 3.2 Genetic Analysis of Depression ............................................................ 25 3.3 Therapeutics and Associated Mechanisms; Pharmacogenetics ............ 27 3.4 Neurogenesis ......................................................................................... 29 3.5 The Endocrine System (hypothalamic-pituitary-adrenal (HPA) axis) .......................................................................................... 31 3.6 Animal Studies ...................................................................................... 33 3.7 Postmortem Brain Studies .................................................................... 36 4 Perspectives ......................................................................................................................... 37 References .......................................................................................................... 38 Dissecting the Molecular Causes of Schizophrenia ...................................... 51 Dieter B. Wildenauer, Diah Mutiara B. Wildenauer, and Sibylle G. Schwab 1 Introduction ................................................................................................ 52 2 Diagnosis .................................................................................................... 52 3 Therapy ...................................................................................................... 52 4 Incidence, Prevalence ................................................................................. 53 5 The Search for Biological Causes ............................................................. 53 6 Epidemiology ............................................................................................. 54 7 Neuropathology .......................................................................................... 56 8 Neurotransmitter Hypotheses .................................................................... 57 vii viii Contents 9 Molecular Genetics .................................................................................... 58 9.1 Localization of Susceptibility Genes by Linkage Analysis ....................................................................... 58 9.2 Genetic Association........................................................................ 59 10 Gene Expression ........................................................................................ 69 10.1 mRNA Expression .......................................................................... 70 10.2 miRNA ........................................................................................... 70 10.3 Protein Expression.......................................................................... 71 10.4 Epigenetics ..................................................................................... 71 11 Animal Models .......................................................................................... 72 12 Conclusion ................................................................................................. 73 References .......................................................................................................... 73 Autism Spectrum Disorders ............................................................................ 81 Sabine M Klauck 1 Introduction ............................................................................................... 81 2 Molecular Genetic Screening.................................................................... 84 2.1 Genome-Wide Screens and Fine-Mapping Approaches ....................................................................................... 84 2.2 Chromosomal Aberrations ................................................................ 88 2.3 Candidate Genes ............................................................................... 89 3 Future Directions ...................................................................................... 91 References .........................................................................................................