Recent Advances in Epilepsy Research

ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY

Editorial Board:

NATHAN BACK, State University of New York at Buffalo

IRUN R. COHEN, The Weizmann Institute of Science

DAVID KRITCHEVSKY, WlStar Institute

ABEL LAITHA, N.S. Kline Institute for Psychiatric Research

RODOLFO PAOLETTI, University of Milan

Recent Volumes in this Series

Volume 533 RETINAL DEGENERATIONS: Mechanisms and Experimental Theory

Edited by Matthew M. LaVail, Joe G. Hollyfield, and Robert E. Anderson

Volume 534 TISSUE ENGINEERING, STEM CELLS, AND GENE THERAPIES

Edited by Y. Murat El in

Volume 535 GLYCOBIOLOGY AND MEDICINE

Edited by John S. Axford

Volume 536 CHEMORECEPTION: From Cellular Signaling to Functional Plasticity

Edited by Jean-Marc Pequignot, Constancio Gonzalez, Colin A. Nurse, Nanduri R. Prabhakar, and Yvette Da1maz

Volume 537 MATHEMATICAL MODELING IN NUTRITION AND THE HEALTH SCIENCES

Edited by Janet A. Novotny, Michael H. Green, and Ray C. Boston

Volume 538 MOLECULAR AND CELLULAR ASPECTS OF MUSCLE CONTRACTION

Edited by Haruo Sugi

Volume 539 BLADDER DISEASE: Research Concepts and Clinical Applications

Edited by Anthony Atala and Debra Slade

Volume 540 OXYGEN TRANSPORT TO TISSUE, VOLUME XXV

Edited by Maureen S. Thorni1ey, David K. Harrison, and Philip E. James

Volume 541 FRONTIERS IN CLINICAL NEUROSCIENCE: Neurodegeneration and Neuroprotection

Edited by L szl V csei

Volume 542 QUALITY OF FRESH AND PROCESSED FOODS

Edited by Fereidoon Shahidi, Arthur M. Spanier, Chi-Tang Ho, and Terry Braggins

A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume inunediately upon publication. Volumes are billed only upon actual shipment. For further information please contact the publisher.

Recent Advances in Epilepsy Research Edited by

Devin K. Binder

Department of Neurological Surgery, University of California at San Francisco, Moffitt Hospital, San Francisco, California, US.A.

Helen E. Scharfman

Center for Neural Recovery and Rehabilitation Research, Helen Hayes Hospital, New York State Department of Health, West Haverstraw, New York, US.A.

Departments of Pharmacology and Neurology, Columbia University, New York, New York, US.A.

Springer Science+Business Media, LLC

Copyright 2004 Springer Science+Business Media New York Origina11y published by Kluwer Academic / Plenum Publishers in 2004

All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher, with the exception of any material supplied specifically for the purpose ofbeing entered and executed on a computer system; for exclusive use by the Purchaser of the work.

ISBN 978-1-4419-3418-5

While the authors, editors and publisher believe that drug selection and dosage and the specifications and usage of equipment and devices, as set forth in this book, are in accord with current recomrnend­ations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book. In view of the ongoing research, equipment development, changes in govemmental regulations and the rapid accumulation of infonnation relating to the biomedica1 sciences, the reader is urged to carefully review and evaluate the information provided herein.

Library of Congress Cataloging-in-Publication Data

Recent advances in epilepsy research / edited by Devin K. Binder, Helen E. Scharfrnan.

p. ; cm. -- (Advances in experimental medicine and biology ; v. 548) Includes bibliographical references and index.

ISBN 978-1-4419-3418-5 ISBN 978-1-4757-6376-8 (eBook) DOI 10.1007/978-1-4757-6376-8

1. Epilepsy--Genetic aspects. 2. Epilepsy--Research. 3. Neuromuscular diseases--Research.

[DNLM: 1. Epilepsy--physiopathology. 2. Epilepsy--genetics. WL 385 R2942003] 1. Binder, Devin K. II. Scharfrnan, Helen E. III. Series. RC372.R382003 616.8'53--dc22

2003022445

INTRODUCTION

Epilepsy research has entered an exciting phase as advances in molecular analysis on a faster and larger scale have supplemented in vitro and in vivo electrophysiologic and phenotypic characterization.

The current volume sets forth a series of chapter reviews by researchers in­volved in these advances. It is not meant to be a comprehensive overview of the field of epilepsy research, but rather a composite profile of some of the recent inves­tigations in certain select areas of enquiry.

Yan Yang and Wayne Frankel describe a genetic approach to studying seizure disorders in mice using a targeted mutagenesis method to exploit the genetic defects identified in human epilepsy families. This includes both the knock-in intro­duction of the human mutations into the corresponding mouse gene as well as analysis of seizure phenotype and the effect of mouse strain background on seizure threshold. Genetic mapping and isolation of the affected genes in these seizure-prone models will enable further characterization of molecular pathways involved in seizures.

Christine Gall and Gary Lynch review the potential contributions of integrins to epileptogenesis. The concept that ultrastructural alterations may interact with functional processes of synaptic plasticity within neurons is supported by observa­tions that integrin adhesion receptors play crucial roles in stabilizing changes in neuronal plasticity. Seizures and even subseizure neuronal activity can modulate the expression of integrins, matrix ligands and proteases. Seizure-induced integrin modulation may contribute to lasting changes underlying epileptogenesis.

Excess activation of growth factors may contribute to hyperexcitability. Devin Binder reviews the biology and pathophysiology of brain-derived neurotrophic fac­tor (BDNF). This ubiquitous neurotrophin is dramatically upregulated following seizures and various studies have shown that BDNF appears to contribute to epileptogenesis. Multiple adult CNS diseases in addition to epilepsy now appear to relate to either a deficiency or excess of BDNF.

Susan Croll, Jeffrey Goodman and Helen Schar/man address the role ofvascu­lar endothelial growth factor (VEGF) after seizures. VEGF induces angiogenesis, vascular permeability, and inflammation. Interestingly, receptors for VEGF have been localized to neurons and glia as well as to vascular endothelium. Croll and colleagues show that there is a striking increase in VEGF protein in both neurons

v

and glia after status epilepticus thus VEGF may contribute to blood-brain barrier breakdown and inflammation observed after seizures.

lonotropic glutamate receptors have long been studied with respect to their contribution to hyperexcitability. Recently, the role of metabotropic (G-protein­coupled) glutamate receptors has also attracted attention. Robert Wong, Shih-Chieh Chuang and Riccardo Bianchi address the modulation of metabotropic glutamate receptors (mGluRs) in epilepsy. In particular, application of group I mGluR ago­nists appears to activate voltage-dependent depolarizing currents that lead to epileptogenesis in vitro.

Recent findings shed new light on the long-studied role of the y-amino-butyric acid (GABA) system in the pathophysiology of epilepsy. George Richerson and Yuanming Wu review the role of the GABA transporter in seizures. Novel anticon­vulsant drugs such as tiagabine appear to block GABA reuptake after synaptic re­lease. Depolarization-induced reversal of the GABA transporter contributing to GABA release is powerfully inhibitory, and is enhanced by the anticonvulsants gabapentin and vigabatrin. Thus, recent data indicate that the GABA transporter plays a critical role not only in tonic inhibition but also in GABA release after seizures.

G nther Sperk , Sabine Furtinger, Christoph Schwarzer and Susanne Pirke re­view the neuropharmacology of GABA and its receptors in epilepsy. Epileptogenesis is associated with loss of a subset of GABAergic neurons as well as altered expres­sion of GABA receptor subunits. Altered physiology and pharmacology of both GABAA and GABAB receptors may contribute to hyperexcitability in hippocampal and cortical networks, and specific knowledge of receptor subtype pharmacology may suggest novel therapeutic targets.

Kevin Staley discusses the role of the depolarizing GABAresponse in epilepsy. First described as a depolarizing response to prolonged application of GABA ago­nists, it can be elicited by focal activation of GABA receptors in dendrites (but not somata) of cultured pyramidal cells. Staley gives a clear explanation of the ionic shifts leading to alteration of the chloride reversal potential and accounting for the depolarizing GABA response. Blockade ofthe depolarizing response to GABA may be the anticonvulsant mechanism of acetazolamide, and may be an appropriate phar­macologic target.

Roger Traub, Hillary Michelson-Law, Andrea Bibbig, Eberhard Buhl, andMiles Whittington summarize the evidence that gap junctions may contribute to epileptogenesis in the hippocampus and cortex. In particular, they describe the dis­covery of a novel class ofaxo-axonal gap junctions that electrically interconnect hippocampal principal neurons. The ability of these gap junctions to promote very high-frequency neuronal oscillations may be critical in precipitating seizures, and thus gap junction inhibitors may be effective anticonvulsants. vi

One field of significant interest to epilepsy is the interaction of nervous and immune systems in the pathophysiology of disease. Annamaria Vezzani, Daniela Moneta, Cristina Richichi, Carlo Perego and Maria Grazia De Simoni review the potential functional role of pro- and anti-inflammatory cytokines in seizures. Cytokines are polypeptide hormones which interact with both neurons and glia, and are produced after limbic status epilepticus. Vezzani et al note the proconvulsant effects of interleukin-l ~ and the anticonvulsant effects of its inhibitor interleukin-l receptor antagonist (IL-lRa).

Deborah Young and Matthew During review studies of the neuroimmunology of epileptic syndromes, in particular recent data on GluR3 autoantibodies in Rasmussen s encephalitis. They have developed a novel approach for epilepsy and stroke treatment using vaccination with NMDARl, and demonstrate that NMDARI vaccination generates autoantibodies to NMDARI that under pathologic conditions block injury-induced neuronal cell death. A vaccine approach is novel as well in that it is potentially prophylactic as well as therapeutic.

Malformations of cortical development (MCD) have received a great deal of recent attention. Philip Schwartzkroin, Steven Roper, and H. Jurgen Wenzel provide a comprehensive overview of MCD syndromes. These syndromes of cortical dys­plasia frequently involve chronic seizures. Their categorization and anatomic and histopathologic features are extensively outlined and discussed. Current animal mod­els of cortical dysplasias are described, which allow investigators to examine the developmental mechanisms that give rise to these brain lesions, and the relationship between structural abnormalities and epileptogenesis.

Peter Crino reviews recent progress regarding the genetics of MCD. Genetic analysis has identified genes for MCD including lissencephaly, subcortical band heterotopia, and tuberous sclerosis. The pathogenesis of other MCD such as focal cortical dysplasia, hemimegalencephaly, and polymicrogyria remains unknown, but new genetic techniques will allow characterization of gene expression within MCD.

Helen Scharftnan addresses the consequences to epilepsy research of the recent recognition of neurogenesis in the adult brain. She describes the observations of neurogenesis after seizures, especially the newly-born dentate granule cells and their potential role in the hippocampal network and in epileptogenesis.

Roland Bender, Celine Dub and Tallie Baram explain the often-cited connec­tion between early febrile seizures and later development oftemporallobe epilepsy (TLE). Their characterization of a novel immature rat model of prolonged febrile seizures has led to insights into the role of complex febrile seizures in hippocampal epileptogenesis.

vii

TIm Benke and John Swann describe the tetanus toxin (TT) model of chronic epilepsy. In this model, tetanus toxin is injected into dorsal hippocampus or neocor­tex, where it is internalized and transported within neurons in which it cleaves synaptobrevin to inhibit release of neurotransmitter. A persistent epileptic state de­velops from a single unilateral hippocampal injection ofTT in infancy.

Jeffrey Goodman reviews a new area that has garnered much attention onate, the use of brain stimulation to treat epilepsy. This area perhaps started with vagus nerve stimulation many years ago, but has recently grown rapidly to include brain targets. These treatments have been remarkably successful and have galvanized a related area of investigation: seizure prediction based on electrographic analysis.

The editors would like to thank all of the authors for their effort and expertise in presenting recent research results, and Ron Landes and Cynthia Conomos for tire­less production assistance and advice.

viii

PARTICIPANTS

Tallie Z. Baram Departments of Anatomy

and Neurobiology, Pediatrics and Neurology

University of California at Irvine Irvine, California USA

Roland A. Bender Departments of Anatomy

and Neurobiology and Pediatrics University of California at Irvine Irvine, California USA

Timothy A. Benke Cain Foundation Laboratories Department of Pediatrics Baylor College of Medicine Houston, Texas USA

Riccardo Bianchi Department of Physiology I

Pharmacology State University of New York Health

Science Center at Brooklyn Brooklyn, New York USA

Andrea E.J. Bibbig Departments of Physiology,

Pharmacology and Neurology SUNY Downstate Medical Center Brooklyn, New York USA

Devin K. Binder Department of Neurological Surgery University of California

at San Francisco Moffitt Hospital San Francisco, California USA

Eberhard H. Buhl School of Biomedical Sciences University of Leeds Leeds England

Shih-Chieh Chuang Department of Physiology I

Pharmacology State University of New York Health

Science Center at Brooklyn Brooklyn, New York USA

ix

x

Peter B. Crino Penn Epilepsy Center

and Department of Neurology University of Pennsylvania

Medical Center Philadelphia, Pennsylvania USA

Susan D. Croll Department of Psychology

and Neuropsychology Doctoral Subprogram

Queens College and the Graduate Center of the City University of New York

Flushing, New York USA Department ofNeuro

and Endocrine Biology Regeneron Pharmaceuticals Tarrytown, New York USA

Maria G. De Simoni Department of Neuroscience Mario Negri Institute

for Pharmacology Research Milano Italy

Celine M. Dub Department of Anatomy

and Neurobiology University of California at Irvine Irvine, California USA

Matthew J. During CNS Gene Therapy Center Department of Neurosurgery Jefferson Medical College Philadelphia, Pennsylvania USA

Wayne N. Frankel The Jackson Laboratory Bar Harbor, Maine USA

Sabine Furtinger

Participants

Department ofPhannacology University of Innsbruck Peter-Mayr-Strasse IA Innsbruck Austria

Christine M. Gall Department of Anatomy

and Neurobiology University of California at Irvine Irvine, California USA

Jeffrey H. Goodman Center for Neural Recovery

and Rehabilitation Research Helen Hayes Hospital New York State Department

of Health West Haverstraw, New York USA

Gary Lynch Department of Psychiatry

and Human Behavior University of California at Irvine Irvine, California USA

Hillary Michelson-Law Departments of Physiology,

Pharmacology and Neurology SUNY Downstate Medical Center Brooklyn, New York USA

Participants

Daniela Moneta Department of Neuroscience Mario Negri Institute

for Pharmacology Research Milano Italy

Carlo Perego Department of Neuroscience Mario Negri Institute

for Pharmacology Research Milano Italy

Susanne Pirker Department of Pharmacology University of Innsbruck Peter-Mayr-Strasse IA Innsbruck Austria

George B. Richerson Departments of Neurology and

Cellular and Molecular Physiology Yale University and Veterans Affairs

Medical Center New Haven, Connecticut USA

Cristina Richichi Department of Neuroscience Mario Negri Institute

for Pharmacology Research Milano Italy

Steven N. Roper Department of Neurological Surgery

and McKnight Brain Institute University of Florida College

of Medicine Gainesville, Florida USA

Helen E. Scharfman Center for Neural Recovery

and Rehabilitation Research Helen Hayes Hospital New York State Department

of Health West Haverstraw, New York USA Departments of Pharmacology

and Neurology Columbia University New York, New York USA

Philip A. Schwartzkroin Department of Neurological Surgery University of California at Davis Davis, California USA

Christoph Schwarzer Department of Pharmacology University ofInnsbruck Peter-Mayr-Strasse IA Innsbruck Austria

G nther Sperk Department of Pharmacology University of Innsbruck Peter-Mayr-Strasse lA Innsbruck Austria

Kevin J. Staley Departments of Neurology

and Pediatrics University of Colorado Health

Sciences Center Denver, Colorado USA

xi

xii

John W. Swann Department of Pediatrics Cain Foundation Laboratories Baylor College of Medicine Houston, Texas USA

Roger D. Traub Departments of Physiology,

Phannacology and Neurology SUNY Downstate Medical Center Brooklyn, New York USA

Annamaria Vezzani Department of Neuroscience Mario Negri Institute

for Phannacology Research Milano Italy

H. Jurgen Wenzel Department of Neurological Surgery University of California at Davis Davis, California USA

Miles A. Whittington School of Biomedical Sciences University of Leeds Leeds England

Participants

RobertK.S. Wong Departments of Physiology I

Phannacology and Neurology State University of New York Health

Science Center at Brooklyn Brooklyn, New York USA

YuanmingWu Departments of Neurology and

Cellular and Molecular Physiology Yale University New Haven, Connecticut USA

Yan Yang The Jackson Laboratory Bar Harbor, Maine USA

Deborah Young Functional Genomics and Translational

Neuroscience Laboratory Department of Molecular Medicine

and Pathology Faculty of Medical and Health

Sciences University of Auckland Auckland New Zealand

CONTENTS

1. GENETIC APPROACHES TO STUDYING MOUSE MODELS OF HUMAN SEIZURE DISORDERS ................................................. 1

Yan Yang and Wayne N. Frankel

Introduction ......................................................................................................................... 1 The Knock-In Technique .................................................................................................... 2 Choosing a Target ................................................................................................................ 2 Phenotypic Characterization of Epileptic Mutant Mice .................................................. 3 Genetic Background on Seizure Phenotyping ................................................................... 6 Summary .............................................................................................................................. 8

2. INTEGRINS, SYNAPTIC PLASTICITY AND EPILEPTOGENESIS ................................................................. 12

Christine M. Gall and Gary Lynch

Abstract .............................................................................................................................. 12 Introduction ....................................................................................................................... 12 Integrins: Cell-Matrix and Cell-Cell Adhesion Receptors ............................................ 13 Integrin Expression in the Adult CNS ............................................................................. 15 Adhesion Proteins Contribute to the Consolidation of Long-Term Potentiation ........ 17 Seizures Activate Changes in Adhesion Chemistries: Evidence for Thrnover

in Adhesive Contacts ................................................................................................. 21 Significance of Seizure-Induced Proteolysis and Adhesion Protein Expression

to Epileptogenesis ...................................................................................................... 24 Concluding Comments ...................................................................................................... 26

3. THE ROLE OF BDNF IN EPILEPSY AND OTHER DISEASES OF THE MATURE NERVOUS SYSTEM ......................................... 34

Devin K. Binder

Abstract .............................................................................................................................. 34 BDNF: Introduction .......................................................................................................... 34 BDNF Structure ................................................................................................................. 34 BDNF Signaling ................................................................................................................. 35 Localization, Transport and Release of BDNF ............................................................... 35 BDNF Effects in Development .......................................................................................... 36 BDNF Gene Regulation ..................................................................................................... 36

xiii

xiv Contents

BDNF, Synaptic Plasticity, and Learning ••••....•.•••••.••.••••••••••..••••••••••.....•••••••....••••••••••..... 37 BDNF and Disease •••••••••••.....•••••••.....••••••••••...•••••••••••••••••••.•...•••••••••••..••••••••••••••••••••••...•••••• 37 BDNF and Epilepsy ........................................................................................................... 37 Effects of Inhibition ofBDNF/trkB in Seizure Models .................................................. 38 Activation of trk Receptors after Seizures •••...••.•.•.•••.•••••••••••.•.••••••••••••....•••••.•...•.•••••••••.. 42 BDNF -Induced Hyperexcitability of the Mossy Fiber-CA3 Synapse ........................... 44 Cellular Model ofBDNF-trkB Interaction .•••••••••••••••••••••....•••••••••••••••.•••••••••••••••••••••.••.••• 45 Other Effects of BDNF •......•••••.........••••.........••••••••••..••.•.......•••••••.•.....•••••••••...••••••••.....•••••• 46 BDNF and Human Epilepsy ••••••.••••••••••••••••••••••••••••••....••••.•••••••••••••••••••••••••••••••••••••••••••.••• 46 BDNF and Other Diseases of the Adult Nervous System ............................................... 47 Summary ...•••.•....••••...•••.....••••.•.....•.•••••..•........•••••••.....•••.•....•••••••••....•..•••••••••...•••••••...••••••••• 48

4. VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) IN SEIZURES: A DOUBLE-EDGED SWORD ................................ 57

Susan D. Croll, Jeffrey H. Goodman and Helen E. Scharfman

Abstract ..••••••••••••••••••••••••••••••••••••••••••••••••••••••••••..•••••••••••••••••••••..•••••••••••....••••••••...•••••••••.•..•• 57 Introduction ....................................................................................................................... 57 Vascular Endothelial Growth Factor (VEGF) ................................................................ 58 VEGF Regulation after Seizures ••••••••••••••••••.......•••••.•.••.•••••••...••••.••••.....••••••••.....••••••......• 60 VEGF As a Neurotrophic Factor •••••••••.••••••••...••••••••••••••••••••••••••••••••••.•••.••••••••..•••••••.••...••• 62 Potential Effects ofVEGF on Seizures and Their Sequelae .......................................... 62

5. PLASTICITY MECHANISMS UNDERLYING mGLUR-INDUCED EPILEPTOGENESIS .......................................................................... 69

Robert K.S. Wong, Shih-Chieh Chuang and Riccardo Bianchi

Abstract •••••••••••••••••..••••.••••••••.••••••••••••.••••••••••••••••••••••••••••••••••...••••••••.•..•••.•••••••.•••••••••••..•••••• 69 Introduction ••....••••••••••...••••••••.•.•••••••••..•.•••••••••.....•.•••••••.•••••••••....•••••••••.......•••••.....•••••••...... 69 Cellular Mechanisms for Group I mGluR-lnduced Excitation

in Hippocampal Neurons ••••••••••••••••••••••••.••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 70 Role of ImG1uR(V) in the Neuronal Activities of Single Pyramidal Cells ........................... 70 Role of ImG1uR(V} in the Generation of Network Activity .................................................. 71 Plasticity Mechanisms Underlying Group I mGluR-lnduced Network

Burst Discharges ....••••••••.•••••••••••.•.••••••••......•.•••••••••.••..••.•..•...•••••••.•...•••••••...••••••.•••...•• 73 Conclusion ..•••.......•••••••.....••••.•....•.••••••....•.....••••...........••••••••••••.....••••••••.•......••••.......•••••...... 74

6. ROLE OF THE GADA TRANSPORTER IN EPILEPSy .......................... 76

George B. Richerson and Yuanming Wu

Abstract ••••.••..•••••••....•••••••••.....•••••.•.....•••••.••....••••••••••••.•••••••••••••••••...•••••••.••.•...•••••••..••••••••.•. 76 Introduction ••...•••••••••••.•••••••••••••••••••••••••••••••••••••••••••••••...•....•••••••••••••••••••••••••••.••••••.•••••••••••• 76 Diversity of GABA Transporters .•••••.••••••••••••.•••••••••••••••••••..•••••••••••••••••.••••••••••••••••••••••••.•• 76 Role of the GABA Transporter in GABA Reuptake ...................................................... 77 Reversal of the GABA Transporter ................................................................................. 77 Functional Significance of GABA Transporter Reversal ............................................... 79 The GABA Transporter As a Target of Anticonvulsants ............................................... 83 Contribution of the GABA Transporter to Tonic GABAergic Inhibition .................... 84 Role of GABA Transporters in Epilepsy •••...••••.•.••••••••••••••••..••••.......••••••.....••.••..•.•••••••...• 87

Contents xv

7. GADAAND ITS RECEPTORS IN EPILEPSy .......................................... 92

G nther Sperk, Sabine Furtinger , Christoph Schwarzer and Susanne Pirker

Abstract .............................................................................................................................. 92 Changes in the Function of GABA Neurons ................................................................... 93 Enhanced Expression of GABA in Dentate Granule Cells ............................................ 94 Altered Expression of GABAA Receptor and Its Subunits in TLE ............................... 95 GAB~ Receptors .••.•..•...••••••••••...•....••.••••••..•......•.••••••••..•.••..••...•.•.•.•.••.••••••.•.••••.•..••...••••••• 98

8. ROLE OF THE DEPOLARIZING GADA RESPONSE IN EPILEPSY ..................................................................................... 104

Kevin J. Staley

9. GAP JUNCTIONS, FAST OSCILLATIONS AND THE INITIATION OF SEIZURES ........................................................... 110

Roger D. Traub, Hillary Michelson-Law, Andrea E.J. Bibbig, Eberhard H. Buhl and Miles A. Whittington

In Vitro Population Activities Paroxysmal to Greater or Lesser Extent Which Depend on Gap Junctions ........................................................................... 110

What Is the Evidence That Principal Cell Gap Junctions Exist? ............................... 116 How Do Axonal Gap Junctions Lead to Very Fast Oscillations? ................................ 116 Gap Junctions and Epileptogenesis in Vivo .................................................................. 117 Summary and Unifying Hypotheses .............................................................................. 117

10. FUNCTIONAL ROLE OF PROINFLAMMATORY AND ANTI-INFLAMMATORY CYTOKINES IN SEIZURES •••••••...•.• 123

Annamaria Vezzani, Daniela Moneta, Cristina Richichi, Carlo Perego and Maria G. De Simoni

Abstract ............................................................................................................................ 123 Introduction •••••••••..•.••.•...•...•..•.••.......•...••.••.••..••.•...•....••••••.•..•••••••..•.•....•..••.••...•....•.••.•.•••• 123 Cytokine Induction by Seizures .....••..••.....•...•....•.•..•.•....••••••..••.••••••....••..•.•..•...•.••.•.••.•.•. 124 Pharmacological Effects: The Focus on IL-l ................................................................ 127 Proinflammatory Cytokines and Nerve Cell Injury ..................................................... 129 Human Epileptic Tissue .................................................................................................. 130 Mechanism of Action .••.•••.•....•.•••••••••••••.••..••.•••••••••••.•..••..•...•.••.•.•.••.•..••..•.••••••.•..•••••••..•.•. 130

11. USING THE IMMUNE SYSTEM TO TARGET EPILEPSy .•...•••••••••• 134

Deborah Young and Matthew J. During

Introduction ..................................................................................................................... 134 Using the Immune System to Treat Neurological Disease The Relationship

between the Brain and the Immune System ......................................................... 134 Using the Immune System to Treat Neurological Disease Therapeutic

Agents for Neurological Disease ............................................................................. 136

xvi Contents

Developing a Vaccine Strategy for Epilepsy .................................................................. 136 A Novel Genetic Vaccine for Stroke and Epilepsy ........................................................ 137 Concluding Remarks ....................................................................................................... 141

12. CORTICAL DYSPLASIA AND EPILEPSY: ANIMAL MODELS •..•... 145

Philip A. Schwartzkroin, Steven N. Roper and H. Jurgen Wenzel

Abstract ............................................................................................................................ 145 What Is Cortical Dysplasia? ..•......•.......•......•.................................................................. 145 What Are the Processes that Lead to Dysplasia? .......................................................... 149 What Makes a Dysplastic Brain (or Brain Region) Epileptic? ................................... 154 Seizure Variability in Dysplastic Brain What Makes a Given Dysplastic

Lesion Epileptogenic? ....•...•......•..•..............••.•.....•...............•.................................. 161 What Do Animal Models of Cortical Dysplasia Tell Us

about Human Epilepsies? ....................................................................................... 163 Concluding Comments ...•.....•......................•...•.........•.......•...•.•..................•.................... 168

13. MALFORMATIONS OF CORTICAL DEVELOPMENT: MOLECULAR PATHOGENESIS AND EXPERIMENTAL STRATEGIES .................................................................................... 175

Peter B. Crino

Abstract ............••.....•........••...•.............................................................•....••...................... 175 Introduction ...........•...................•...•...........•......•.•.....................•..................•............•...... 175 Important Clinical Issues in Patients with MCD ......................................................... 176 Developmental Contextual Background for MCD ....................................................... 176 Molecular Neurobiology of MCD ...........................................•..............•........................ 178 Epileptogenesis and MCD: How Does Cortical Maldevelopment Lead

to Epilepsy? .............................................................................................................. 183 Experimental Strategies for Studying Epilepsy in MCD ............................................. 185 Conclusions .......•.....••........•.•....•..••.....•.........•...........•.....•.•..........•.................................... 187 Summary and New Directions: Targeted Therapy for Epilepsy in MCD ............•..... 187

14. FUNCTIONAL IMPLICATIONS OF SEIZURE-INDUCED NEUROGENESIS .•••.....•......•.......•.•..........•........•.......•.......•.....••........ 192

Helen E. Scharfman

Abstract .•..............••...•..........•.•.....••.............•........•........................•..............•................... 192 Introduction ..................................................................................................................... 192 Proving That Granule-Like Cells in the Hilus after Seizures Were Newly-Born

Granule Cells ........................................................................................................... 194 Do All the New Granule Neurons Become Functional? Do They Behave

the Same? ..............•..............................•...................•..........•.........•..............•........... 198 Is Increased Neurogenesis Beneficial, or Might It Actually Increase

Seizure Susceptibility? ..................................•......................•.................................. 200 How Do the New Cells Interact with the Host Brain? ................................................. 204 Is Neurogenesis Increased after Seizures in Man? ....................................................... 207 Summary .......................................................................................................................... 207

Contents xvii

15. FEBRILE SEIZURES AND MECHANISMS OF EPILEPTOGENESIS: INSIGHTS FROM AN ANIMAL MODEL •••••••••..•.••.•••••••••.••••••••••••••••••..••••••••••••••••.•••.•••• 213

Roland A. Bender, Celine Dub and Tallie Z. Baram

Abstract ............................................................................................................................ 213 Introduction: The Human Problem ••••••••••...••..•..••...••••••••..•••••••••..•.••..••.•••••..•.•••.••.•..••••• 213 The Optimal Animal Model .••.•.•..•.•.••••••.•••.•...•..••.•...•.•..•.•.•.•••.••.••.•...•..•...•.••..••.•..•.••..• 214 The Immature Rat Model ............................................................................................... 217 Do Prolonged Experimental Febrile Seizures Increase Seizure Susceptibility? ..•...•. 219 Do Prolonged Experimental Febrile Seizures Cause Neuronal Death

and/or Synaptic Reorganization? .••.•.•.•...•..••...••..•..•.•••.••..••.••••.•.•..•...•••••.••••....••..••• 220 Do Prolonged Experimental Febrile Seizures Alter the Rate of Granule

CeU Neurogenesis? ••.•.••••••.••.••....••••••••...•...•.•••••••••••..•.•.•••••.••.•........••.•.•.••.•••.•..•.••••.•. 220 Molecular Plasticity after Experimental Prolonged Febrile Seizures ..•.••.•.•.••••....•.•.• 221 Summary .••.•......•.•••.•..•...••••••.•.••••••.•.••..••.••..••.•••••••..•.....•.••...•.•••.••.•.••...•.•...••.•.•••..•.•........• 221

16. THE TETANUS TOXIN MODEL OF CHRONIC EPILEPSy •...••••.•••• 226

Timothy A. Benke and John Swann

Introduction ...•.•.•.••.•..•...••••..••.•...•..•..•...•.•.••••.•.•.•...•....••.•..••.••...•.••.•••••..•...•.•••••••••.....••...•. 226 Mechanisms of Tetanus Toxin ........................................................................................ 226 Experimental Implementation ....................................................................................... 230 Chronic Epilepsy in Adult Animals ................................................................................ 230 Chronic Epilepsy in Young Animals .............................................................................. 233 Comparisons to Other Models of Chronic Epilepsy ..................................................... 235

17. BRAIN STIMULATION AS A THERAPY FOR EPILEPSy ................ 239

Jeffiey H. Goodman .................................................................................................. 239

Abstract ............................................................................................................................ 239 Introduction ..................................................................................................................... 239 Vagus Nerve Stimulation ................................................................................................. 240 DBS As a Therapy for Epilepsy ...................................................................................... 241 Activation of Seizure-Gating Networks Animal Studies ........................................... 241 Activation of Seizure-Gating Networks Clinical Studies .......................................... 242 Focal Stimulation ............................................................................................................. 242 Selection of Stimulation Parameters .............................................................................. 242 Safety ................................................................................................................................ 243 The Future Is Now: Seizure Prediction Combined with Pre-Emptive

Stimulation ............................................................................................................... 243 Conclusion ........................................................................................................................ 244

INDEX ............................................................................................................... 249