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

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) 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.

SUBMITTER: Kurita M

PROVIDER: S-EPMC3431440 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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

Kurita Mitsumasa M Holloway Terrell T García-Bea Aintzane A Kozlenkov Alexey A Friedman Allyson K AK Moreno José L JL Heshmati Mitra M Golden Sam A SA Kennedy Pamela J PJ Takahashi Nagahide N Dietz David M DM Mocci Giuseppe G Gabilondo Ane M AM Hanks James J Umali Adrienne A Callado Luis F LF Callado Luis F LF Gallitano Amelia L AL Neve Rachael L RL Shen Li L Buxbaum Joseph D JD Han Ming-Hu MH Nestler Eric J EJ Meana J Javier JJ Russo Scott J SJ González-Maeso Javier J

Nature neuroscience 20120805 9

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 ...[more]

PMID: 22864611

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

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

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