Dr. Perrone-Bizzozero and W. Michael Bullock Reply

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 GAD ₆₇ (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 GAD ₆₇ 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 GAD ₆₇ 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.