CORTICAL DEFICITS IN SCHIZOPHRENIA From Genes to Function

Transcription

1 CORTICAL DEFICITS IN SCHIZOPHRENIA From Genes to Function

2 CORTICAL DEFICITS IN SCHIZOPHRENIA From Genes to Function Edited by Patricio O Donnell University of Maryland, Baltimore, MD, USA

3 Patricio O Donnell Depts. Anatomy & Neurobiology and Psychiatry University of Maryland School of Medicine 20 Penn Street, Room S251 Baltimore, MD Library of Congress Control Number: ISBN-13: e-isbn-13: Printed on acid-free paper Springer Science+Business Media, LLC All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights springer.com

4 Contents List of Contributors...vii Preface...xi Foreword...xiii 1. Schizophrenia Genes: Searching for Common Features, Functions, and Mechanisms...1 Paul J. Harrison 2. Towards a Molecular Classification of Illness: Effects of Schizophrenia Susceptibility Loci on Clinical Symptoms and Cognitive Function...17 Anil K. Malhotra, Pamela DeRosse and Katherine E. Burdick 3. Homer: A Genetic Factor in Schizophrenia?...29 Karen K. Szumlinski and Todd E. Kippin 4. Neuregulin-erbB Signaling and the Pathogenesis of Schizophrenia...73 Christine Roy and Gabriel Corfas 5. Nicotinic Cholinergic Cortical Dysfunction in Schizophrenia...97 Jason R. Tregellas and Robert Freedman 6. A Role for Glutamate Receptors, Transporters, and Interacting Proteins in Cortical Dysfunction in Schizophrenia Deborah Bauer, Robert E. McCullumsmith and James H. Meador- Woodruff

5 vi Contents 7. Cortical Circuit Dysfunction in the NMDA Receptor Hypofunction Model for the Psychosis of Schizophrenia Robert Greene 8. Alterations in Hippocampal Function in Schizophrenia: its Genetic Associations and Systems Implications Subroto Ghose and Carol A. Tamminga 9. Identifying Novel Target Genes in Psychotic Disorder Network Association Analyses Francine M. Benes, Benjamin Lim, David Matzilevich and John Walsh 10. Alterations in Cortical GABA Neurotransmission in Schizophrenia: Causes and Consequences David A. Lewis, Takanori Hashimoto, Jaime G. Maldonado-Aviles and Harvey Morris 11. Increased Cortical Excitability as a Critical Element in Schizophrenia Pathophysiology Patricio O Donnell Index...237

6 List of Contributors Deborah Bauer University of Alabama at Birmingham, Department of Psychiatry rd Avenue South, Birmingham, AL 35294, USA Francine Benes McLean Hospital, Program in Structural and Molecular Neuroscience 115 Mill St., Belmont, MA 02478, USA Katherine E. Burdick Zucker Hillside Hospital, Division of Psychiatry Research Glen Oaks, NY, 11004, USA Gabriel Corfas Harvard University, Children s Hospital, Neurobiology Program 300 Longwood Ave, Boston, MA 02115, USA Pamela DeRosse Zucker Hillside Hospital, Division of Psychiatry Research Glen Oaks, NY, 11004, USA Robert Freedman University of Colorado, Department of Psychiatry Campus Box C249-32, Denver, CO 80111, USA Subroto Ghose University of Texas Southwestern, Department of Psychiatry 5323 Harry Hines Blvd. Dallas, TX 75390, USA Robert W. Greene University of Texas Southwestern, Department of Psychiatry 5323 Harry Hines Blvd. Dallas, TX 75390, USA

7 viii List of Contributors Paul J. Harrison University of Oxford, Department of Psychiatry, Warneford Hospital Oxford OX3 7JX, United Kingdom Takanori Hashimoto University of Pittsburgh, Department of Psychiatry 3811 O Hara St., Pittsburgh, PA 15213, USA Todd E. Kippin University of California at Santa Barbara, Dept Psychology Santa Barbara, CA 93106, USA David A. Lewis University of Pittsburgh, Department of Psychiatry 3811 O Hara St., Pittsburgh, PA 15213, USA Benjamin Lim McLean Hospital, Program in Structural and Molecular Neuroscience 115 Mill St., Belmont, MA 02478, USA Jaime G. Maldonado-Aviles University of Pittsburgh, Department of Psychiatry 3811 O Hara St., Pittsburgh, PA 15213, USA Anil K. Malhotra Zucker Hillside Hospital, Division of Psychiatry Research Glen Oaks, NY, 11004, USA David Matzilevich McLean Hospital, Program in Structural and Molecular Neuroscience 115 Mill St., Belmont, MA 02478, USA Robert E. McCullumsmith University of Alabama at Birmingham, Department of Psychiatry rd Avenue South, Birmingham, AL 35294, USA James H. Meador-Woodruff University of Alabama at Birmingham, Department of Psychiatry rd Avenue South, Birmingham, AL 35294, USA Harvey Morris University of Pittsburgh, Department of Psychiatry 3811 O Hara St., Pittsburgh, PA 15213, USA Patricio O'Donnell University of Maryland School of Medicine 20 Penn St., Baltimore, MD 21286, USA Christine Roy Harvard University, Children s Hospital, Neurobiology Program 300 Longwood Ave, Boston, MA 02115, USA

8 List of Contributors ix Karen K. Szumlinski University of California at Santa Barbara, Dept Psychology Santa Barbara, CA 93106, USA Carol A. Tamminga University of Texas Southwestern, Department of Psychiatry 5323 Harry Hines Blvd. Dallas, TX 75390, USA Jason R. Tregellas University of Colorado, Department of Psychiatry Campus Box C249-32, Denver, CO 80111, USA John Walsh McLean Hospital, Program in Structural and Molecular Neuroscience 115 Mill St., Belmont, MA 02478, USA

9 Preface The genetics of schizophrenia have taken the driver seat in the research related to this disorder in recent years. For a long time, it had been known that sharing genes with someone affected with schizophrenia conferred a 50% chance of acquiring the disease. Although this is fifty times the incidence in the normal population, it was evident that genes could not explain all factors involved. At best, one could think of a combination of gene traits conferring predisposition for the disease. Now, it is evident that although there are no genes that individually confer a strong liability, several candidate gene alleles do confer some risk, and perhaps a combination of genes could cause the emergence of symptoms in this multi-faceted psychiatric condition. As the research on predisposing genes soars, it is becoming clear that we need to be able to identify cellular processes the genes control and to provide pathophysiological scenarios that could link those cellular phenomena with symptoms. In this book, we have chosen to elaborate on that link. The contributions to this book have been requested to reflect the current state of the connection between schizophrenia genetics and pathophysiology. The book opens with a chapter by Paul Harrison highlighting the several convergence points among the diverse schizophrenia-related genes. This is followed by chapters reviewing several different specific genes, including Neuregulin, DISC-1, dysbindin, and Homer, among others, and by several chapters presenting information on physiological cortical processes that could be affected by those genes. These include glutamatergic, GABAergic and cholinergic neurotransmission. Current hot topics in schizophrenia research are also highlighted in the book. A concept that is gaining strength in the field, for example, is the role of inhibitory neurotransmission in schizophrenia pathophysiology, with converging (and convincing) data from post-mortem and imaging studies. The

10 xii Preface possibility of deficits in cortical inhibition (causing the emergence of noisy cortical activity) is discussed throughout the book in relationship with possible alterations in GABA and/or glutamate activity in several cortical areas including the prefrontal cortex and the temporal lobe. Thus, the chapters in this book summarize the current state of affairs in schizophrenia pathophysiology, with a consideration of genetic elements that may contribute to it. This timely book could prove a useful tool for those interested in a better understanding of schizophrenia. Even if more predisposing genes (not included in this book) become identified, the work laid out here will prove critical for assigning a functional (or dysfunctional) role to those genes. Although this is a fast-evolving field, the information and concepts covered in this book will likely be useful for years to come. Patricio O Donnell, MD, PhD

11 Foreword The genetics of schizophrenia have taken the driver seat in recent years in the research related to this disorder. For a long time, it had been known that sharing genes with someone affected with schizophrenia conferred a 50% chance of acquiring the disease. Although this is 50 times the incidence in the normal population, it was evident that genes could not explain all factors involved. At best, one could think of a combination of gene traits conferring predisposition for the disease. Now, it is evident that although there are no genes conferring a strong liability independently, several candidate gene alleles do confer risk, and perhaps a combination of several genes could cause the emergence of symptoms in this multi-faceted psychiatric condition. As the research on predisposing genes soars, it is becoming clear that we need to be able to provide pathophysiological scenarios that could link the cellular phenomena the genes control with symptoms. In this book, we have chosen to elaborate on that link.