Expression of GAD1 GABA synthesis enzyme is highly regulated by
neuronal activity and reaches mature levels in prefrontal cortex not before adolescence. A
significant portion of cases diagnosed with schizophrenia show deficits in
GAD1 RNA and protein levels in multiple areas of adult cerebral cortex,
possibly reflecting molecular or cellular defects in subtypes of GABAergic interneurons
essential for network synchronization and cognition. Here, we review 20 years of progress
towards a better understanding of disease-related regulation of GAD1 gene
expression. For example, deficits in cortical GAD1 RNA in some cases of
schizophrenia are associated with changes in the epigenetic architecture of the promoter,
affecting DNA methylation patterns and nucleosomal histone modifications. These localized
chromatin defects at the 5′end of GAD1 are superimposed by
disordered locus-specific chromosomal conformations, including weakening of long-range
promoter-enhancer loopings and physical disconnection of GAD1 core
promoter sequences from cis-regulatory elements positioned 50 kilobases further upstream.
Studies on the 3-dimensional architecture of the GAD1 locus in neurons,
including developmentally regulated higher order chromatin compromised by the
disease process, together with exploration of locus-specific epigenetic interventions in
animal models, could pave the way for future treatments of psychosis and
schizophrenia.