To the Editor: We fully agree with Dr. Peedicayil that epigenetic mechanisms play an important role in the control of gene expression and that defects in these processes are associated with an increasing number of mental disorders. Moreover, recent reports suggest that reduced expression of GAD67 (the GABA synthesizing enzyme encoded by the GAD1 gene) in schizophrenia patients is associated with both specific polymorphisms in the promoter region (1) and altered epigenetic regulation (2, 3), and we apologize for the oversight of not citing the latter in our article. However, we wish to clarify that it was not our intention to propose a mechanism for the decreases in GAD67 in schizophrenia but to put these changes in the context of neuronal circuitry (4). Specifically, our goal was to investigate gene expression alterations as they relate to a dysfunction in GABAergic and glutamatergic transmission in the cerebellum of individuals with schizophrenia. Our results strongly suggest that Golgi cells, which are the GABAergic interneurons that inhibit granule cell activity, are affected in schizophrenia. These results not only explain our previous observation of increased activity-dependent granule cell gene expression in schizophrenia (5) but also give further support to the hypothesis that some subtypes of GABAergic interneurons may be compromised in this illness. Along these lines, we recently found that Golgi cells are primarily affected by chronic intermittent exposure to relatively low doses of phencyclidine (data available upon request from W.M. Bullock et al.), suggesting that N-methyl-d-aspartic acid hypofunction could lead to decreases in GABA synthesis and neurotransmission in schizophrenia. Moreover, we feel that it is very important to determine the causes of the decrease in GAD67 mRNA in postmortem cerebellar tissue, and we plan to address whether these deficits are associated with genetic factors and/or epigenetic dysregulation in future studies.
1.Straub RE, Lipska BK, Egan MF, Goldberg TE, Callicott JH, Mayhew MB, Vakkalanka RK, Kolachana BS, Kleinman JE, Weinberger DR: Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression. Mol Psychiatry 2007; 12:854–8692.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; 2:29–363.Huang HS, Matevossian A, Whittle C, Kim SY, Schumacher A, Baker SP, Akbarian S: Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters. J Neurosci 2007; 27:11254–112624.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; 165:1594–16035.Paz RD, Andreasen NC, Daoud SZ, Conley R, Roberts R, Bustillo J, Perrone-Bizzozero NI: Increased expression of activity-dependent genes in cerebellar glutamatergic neurons of patients with schizophrenia. Am J Psychiatry 2006; 163:1829–1831
The authors’ disclosures accompany the original article.
This letter (doi: 10.1176/appi.ajp.2009.09010011r) was accepted for publication in February 2009.