Histone deacetylases (HDACs) compact chromatin structure and repress gene transcription. In schizophrenia, clinical studies demonstrate that HDAC inhibitors are efficacious when given in combination with atypical antipsychotics. However, the molecular mechanism that integrates a better response to antipsychotics with changes in chromatin structure remains unknown. Here we found that chronic atypical antipsychotics downregulated the transcription of metabotropic glutamate 2 receptor (mGlu2, also known as Grm2), an effect that was associated with decreased histone acetylation at its promoter in mouse and human frontal cortex. This epigenetic change occurred in concert with a serotonin 5-HT2A receptor–dependent upregulation and increased binding of HDAC2 to the mGlu2 promoter. Virally mediated overexpression of HDAC2 in frontal cortex decreased mGlu2 transcription and its electrophysiological properties, thereby increasing psychosis-like behavior. Conversely, HDAC inhibitors prevented the repressive histone modifications induced at the mGlu2 promoter by atypical antipsychotics, and augmented their therapeutic-like effects. These observations support the view of HDAC2 as a promising new target for schizophrenia treatment.
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The authors would like to thank A. Chess, Y. Hurd, C. Alberini, P. Bos and J. Greally for critical review of the manuscript; M. Shapiro for help in working memory experiments; S. Morgello (Mount Sinai School of Medicine) and the Manhattan HIV Brain Bank for providing control brain cortex; P. Casaccia (Mount Sinai School of Medicine) for discussions and for providing the plasmid encoding mouse HDAC2; J. Gingrich (Columbia University) for his gift of 5HT2A−/− mice; V. Rayannavar for assistance with biochemical and behavioral assays; and the staff members of the Basque Institute of Legal Medicine for their cooperation in the study. US National Institutes of Health (NIH) R01 MH084894 (J.G.-M.), Dainippon Sumitomo Pharma (J.G.-M.), NARSAD (J.G.-M.), the Maltz Family Foundation (J.G.-M.), NIH R01 MH090264 (S.J.R.), MICINN SAF2009-084609 (J.J.M.), the Basque Government IT-199-07 (J.J.M.), NIH P50 MH090963 (E.J.N.), NIH R01 MH092306 (M.-H.H.) and NIH P50 MH066392 (J.D.B.) helped fund this study. A.K.F. was supported by NIH grant F32 MH096464. A.G.-B., J.L.M. and G.M. were recipients of predoctoral and postdoctoral fellowships from the Basque government, Ministerio de Ciencia e Innovación, and Consejo Superior de Investigaciones Científicas (CSIC), Spain.
The authors declare no competing financial interests.
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Kurita, M., Holloway, T., García-Bea, A. et al. HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nat Neurosci 15, 1245–1254 (2012). https://doi.org/10.1038/nn.3181
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