title: Antipsychotic subtypes can be characterized by differences in their ability to modify GABAergic promoter methylation.
abstract: Recent advances in schizophrenia and bipolar disorder research suggest that a dysfunction of GABAergic neurotransmission that is operative in telencephalic structures may be an important dynamic mechanism associated with psychosis. We propose that this dysfunction is probably mediated by the hypermethylation of glutamic acid decarboxylase (GAD67), reelin and other gene promoters expressed in GABAergic neurons. A pharmacological strategy that reduces the hypermethylation of GABAergic promoters is to administer drugs (i.e., valproate [VPA]) that induce DNA demethylation by facilitating chromatin remodeling. The enhanced clinical efficacy of atypical antipsychotics when co-administered with VPA prompted us to investigate whether this increased drug efficacy is related to a modification of GABAergic promoter methylation via chromatin remodeling. Our previous and present results strongly suggest that when associated with VPA, clozapine or sulpiride, but not haloperidol or olanzapine, facilitate chromatin remodeling. This molecular remodeling may contribute to the induction of reelin (RELN) and GAD(67) (GAD1) promoter demethylation, and may reverse the downregulation of various GABAergic mRNAs and proteins detected in the telencephalon of patients with schizophrenia or bipolar disorders.
authors: College of Medicine, Psychiatric Institute, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA.
authors: Erbo
authors: E
authors: Dong
authors: Dennis R
authors: DR
authors: Grayson
authors: Alessandro
authors: A
authors: Guidotti
authors: Erminio
authors: E
authors: Costa
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D059330:GABAergic Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000091042:Reelin Protein; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D004248:DNA (Cytosine-5-)-Methyltransferases; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D005968:Glutamate Decarboxylase