title: DNA methylation and demethylation as targets for antipsychotic therapy.
abstract: Schizophrenia (SZ) and bipolar disorder (BPD) patients show a downregulation of GAD67, reelin (RELN), brain-derived neurotrophic factor (BDNF), and other genes expressed in telencephalic GABAergic and glutamatergic neurons. This downregulation is associated with the enrichment of 5-methylcytosine and 5-hydroxymethylcytosine proximally at gene regulatory domains at the respective genes. A pharmacological strategy to reduce promoter hypermethylation and to induce a more permissive chromatin conformation is to administer drugs, such as the histone deacetylase (HDAC) inhibitor valproate (VPA), that facilitate chromatin remodeling. Studies in mouse models of SZ indicate that clozapine induces DNA demethylation at relevant promoters, and that this action is potentiated by VPA. By activating DNA demethylation, clozapine or its derivatives with VPA or other more potent and selective HDAC inhibitors may be a promising treatment strategy to correct the gene expression deficits detected in postmortem brain of SZ and BPD patients.
authors.affiliation: Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Illinois, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Guidotti
authors.affiliation: Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Illinois, USA.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Grayson
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D001523:Mental Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D000091042:Reelin Protein
chemical_list: D014150:Antipsychotic Agents; D000091042:Reelin Protein; C000717127:RELN protein, human; C000717128:Reln protein, mouse
keywords: bipolar; chromatin remodeling; clozapine epigenetics; histone deacetylase inhibitor; neuroleptic; psychosis; schizophrenia