Epigenetic Animal Models of GABAergic Deficit in Mental Disorders

There is substantial evidence that psychosis is characterized by GABAergic gene promoters that are in a closed chromatin state, leading to reduced transcription of proteins essential for GABAergic and synaptic function in the forebrain. Two critical genes that are downregulated in cortical and hippocampal interneurons by 30–50% in psychotic postmortem brain are GAD1 , the gene for GAD67, and RELN , the gene for reelin. The promoter region of these genes is vulnerable to cytosine methylation by DNA methyltransferases, enzymes that in psychosis are elevated in GABAergic interneurons. An alteration in histone deacetylase or methyltransferase expression provides further evidence for an underlying epigenetic etiology. Animal models aimed at studying the epigenetic basis for key phenotypic components of psychiatric illness have involved the following: (1) administering drugs affecting epigenetic processes, e.g., repeated corticosterone or l -methionine administration to induce a disease state or histone deacetylase inhibitors or nicotinic agonists to reverse the abnormality, or (2) manipulating the natural environment, e.g., by social isolation/enrichment, social dominance/defeat, or chronic exposure to stress early in development prenatally or by maternal care.