Epigenetic Downregulation of GABAergic Function in Schizophrenia: Potential for Pharmacological Intervention?

Abstract

Although the propensity to develop schizophrenia has long been attributed in part to a “genetic” component, this component does not follow Mendelian laws and may be primarily epigenetic. We have detected a decrease in levels of mRNA encoding the 67-kDa glutamate decarboxylase (GAD₆₇), but not of that encoding GAD₆₅, in several cortical areas from the brains of patients afflicted with either schizophrenia or bipolar disorder, but not from patients with severe depression. In addition, dendritic levels of reelin (and the mRNA that encodes it), a protein essential to neurodevelopment, are decreased in schizophrenia. We have further investigated whether hypermethylation of the genes that encode the GADs and reelin might be at the root of the observed decreases in corresponding mRNA. Indeed, administration of methionine, a source of methyl groups in multiple enzymatic reactions, causes a recrudescence of schizophrenic symptoms, and we have correlated high intake of methionine in mice with both an increase in levels of promoter methylation and a decrease in production of reelin and GAD₆₇. This decrease is reversed by treatment with valproate, an inhibitor of histone deacetylase.