HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity

Mitsumasa Kurita, Terrell Holloway, Aintzane GarcÃ- A-Bea, Alexey Kozlenkov, Allyson K. Friedman, José L. Moreno, Mitra Heshmati, Sam A. Golden, Pamela J. Kennedy, Nagahide Takahashi, David M. Dietz, Giuseppe Mocci, Ane M. Gabilondo, James Hanks, Adrienne Umali, Luis F. Callado, Amelia L. Gallitano, Rachael L. Neve, Li Shen, Joseph D. BuxbaumMing Hu Han, Eric J. Nestler, J. Javier Meana, Scott J. Russo, Javier González-Maeso

Research output: Contribution to journalArticle

177 Scopus citations

Abstract

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-HT 2A receptorg-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.

Original languageEnglish (US)
Pages (from-to)1245-1254
Number of pages10
JournalNature neuroscience
Volume15
Issue number9
DOIs
StatePublished - Sep 1 2012

ASJC Scopus subject areas

  • Neuroscience(all)

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    Kurita, M., Holloway, T., GarcÃ- A-Bea, A., Kozlenkov, A., Friedman, A. K., Moreno, J. L., Heshmati, M., Golden, S. A., Kennedy, P. J., Takahashi, N., Dietz, D. M., Mocci, G., Gabilondo, A. M., Hanks, J., Umali, A., Callado, L. F., Gallitano, A. L., Neve, R. L., Shen, L., ... González-Maeso, J. (2012). HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nature neuroscience, 15(9), 1245-1254. https://doi.org/10.1038/nn.3181