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, GAD65, and GAD67. 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 GAD65 and GAD67. 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).
1.Bullock WM, Cardon K, Bustillo J, Roberts RC, Perrone-Bizzozero NI: Altered expression of genes involved in GABAergic transmission and neuromodulation of granule cell activity in the cerebellum of schizophrenia patients. Am J Psychiatry 2008; 165:1594–16032.Peedicayil J: The role of epigenetics in mental disorders. Indian J Med Res 2007; 126:105–1113.Abdolmaleky HM, Zhou JR, Thiagalingam S, Smith CL: Epigenetic and pharmacoepigenomic studies of major psychoses and potentials for therapeutics. Pharmacogenomics 2008; 9:1809–18234.Costa E, Dong E, Grayson DR, Guidotti A, Ruzicka W, Veldic M: Reviewing the role of DNA (cytosine-5) methyltransferase overexpression in the cortical GABAergic dysfunction associated with psychosis vulnerability. Epigenetics 2007; 2:29–365.Peedicayil J, Thangavelu P: Purkinje cell loss in autism may involve epigenetic changes in the gene encoding GAD. Med Hypotheses 2008; 71:978
The author reports no competing interests.
This letter (doi: 10.1176/appi.ajp.2009.09010011) was accepted for publication in February 2009.