Epigenetic Targets in GABAergic Neurons to Treat Schizophrenia

E. Costa, E. Dong, D. R. Grayson, W. B. Ruzicka, M. V. Simonini, M. Veldic, and A. Guidotti

I. Chapter Overview 95

II. Introduction 96

III. Regulation of Histone Acetylation 98

IV. Chromatin Remodeling at Neuromuscular Junction 98

V. Chromatin Remodeling During Memory Formation 99

VI. Role of Reelin and Apolipoprotein E Receptors in Hippocampal

Plasticity and Learning 101 VII. Is Reelin Expressed Only in a Selective Subpopulation of GABAergic Neurons? 103

VIII. RELN and GAD67 CpG Island Promoter Hypermethylation and

Reelin and GAD67 Expression Downregulation in SZ Patients 104 IX. Increased DNA-Methyltransferase-1 Expression in Cortical GABAergic Neurons of SZ Patients 105

X. Relationship Between DNMT1 Overexpression and Reelin and

GAD67 Downregulation in GABAergic Neurons of SZ Patients 106

XI. Pharmacological Strategies to Reduce Reelin and GAD67 Promoter Hypermethylation in SZ Patients 107

XII. The MET-Induced Epigenetic Mouse Model to Evaluate Prospective HDAC Inhibitors to be Used to Influence Epigenetic Mechanisms in Cortical GABAergic Neurons 110

XIII. Conclusions 111 References 112

GABAergic Malfunction in the Limbic System Resulting from an Aboriginal Genetic Defect in Voltage-Gated Na+-Channel SCN5A is Proposed to Give Rise to Susceptibility to Schizophrenia

Eugene Roberts

I. Chapter Overview 119

II. Introduction 120

III. Levels of Concern 123

IV. The Hypothalamo-Hypophyseal System 129

V. The Cybernins 130

VI. A Failed Therapeutic Adventure 132

VII. Linkage of Propranolol Cognitive Effects with Correction of a Limbic System Defect that Results in Failure of Habituation in Schizophrenia (see Gruzelier, 1978) 135

VIII. Susceptibility to Schizophrenia may Result from Mutation of the Na+ Channel-Coding SCN5A Gene, Which Occurs at Uniquely High Levels in Neural Components of the Limbic System 137

IX. Recyberneticizing Substances and Mechanisms of Their Action 139

X. Problems in Therapy with Racemic Propranolol 141

XI. The GABA System and Schizophrenia 141 References 144

GABAa Receptor Mutations Associated with Generalized Epilepsies

(This is a revised and updated version of an article entitled ''GABAa receptor epilepsy mutations'' that appeared in Biochem. Pharmacol. 68, 1497-1506 (2004).)

Robert L. Macdonald, Jing-Qiong Kang, Martin J. Gallagher, and Hua-Jun Feng

I. Chapter Overview 147

II. GABAa Receptors 148

III. GABAA Receptor Epilepsy Genes 149

IV. Conclusions 165 References 167

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