Journal
NATURE NEUROSCIENCE
Volume 15, Issue 9, Pages 1245-U109Publisher
NATURE PORTFOLIO
DOI: 10.1038/nn.3181
Keywords
-
Categories
Funding
- US National Institutes of Health (NIH) [R01 MH084894]
- Dainippon Sumitomo Pharma
- NARSAD
- Maltz Family Foundation
- NIH [R01 MH090264, P50 MH090963, R01 MH092306, P50 MH066392, F32 MH096464]
- MICINN [SAF2009-084609]
- Basque Government [IT-199-07]
- Ministerio de Ciencia e Innovacion
- Consejo Superior de Investigaciones Cientificas (CSIC), Spain
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available