The Role of Epigenetics in Altered Gene Expression Involved in GABAergic Transmission in the Cerebellum of Schizophrenia Patients

To the Editor: In their article, published in the December 2008 issue of the Journal , W. Michael Bullock et al. (1) reported reduced expression of genes involved in gamma-aminobutyric acid (GABA)-ergic transmission in the postmortem cerebellum of individuals with schizophrenia relative to postmortem comparison subjects without a history of psychiatric illness. Bullock et al. found reduced expression of genes encoding the two isoforms of glutamic acid decarboxylase (GAD), which is the enzyme that catalyzes the conversion of L-glutamic acid to GABA, GAD ₆₅ , and GAD ₆₇ . These changes were found to be associated with compensatory changes in the expression of other genes. The authors did not determine the cause of the reduced expression of genes encoding GAD ₆₅ and GAD ₆₇ . However, the introduction section of their article implied that genetic factors, such as genetic polymorphisms, could be the cause of this reduced expression.

Another possibility regarding the cause of reduced expression of genes involved in GABAergic transmission in the cerebellum of schizophrenia subjects examined in their study might involve epigenetics (i.e., heritable changes in gene expression not involving changes in DNA sequence). Epigenetics engages at least the following three interacting molecular mechanisms: DNA methylation, histone modification, and RNA-mediated regulation of gene expression (2) . This suggestion is based on the fact that, to date, no genetic mutation or polymorphism predisposing to the pathogenesis of schizophrenia has been found (2 , 3) . In addition, there is increasing evidence that epigenetics plays a major role in the pathogenesis of schizophrenia and other idiopathic mental disorders (2 , 3) . Moreover, the promoter of the gene encoding GAD has been shown to be epigenetically modified in the cerebral cortex in schizophrenia patients, resulting in reduced expression of GAD (2 , 4) . Last, there is evidence suggesting that the gene encoding GAD is epigenetically modified in the cerebellum in individuals with autism, causing reduced expression of GAD (5) .