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HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity
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 a...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431440/ https://www.ncbi.nlm.nih.gov/pubmed/22864611 http://dx.doi.org/10.1038/nn.3181 |
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author | Kurita, Mitsumasa Holloway, Terrell García-Bea, Aintzane Kozlenkov, Alexey Friedman, Allyson K. Moreno, José L. Heshmati, Mitra Golden, Sam A. Kennedy, Pamela J. Takahashi, Nagahide Dietz, David M. Mocci, Giuseppe Gabilondo, Ane M. Hanks, James Umali, Adrienne Callado, Luis F. Gallitano, Amelia L. Neve, Rachael L. Shen, Li Buxbaum, Joseph D. Han, Ming-Hu Nestler, Eric J. Meana, J. Javier Russo, Scott J. González-Maeso, Javier |
author_facet | Kurita, Mitsumasa Holloway, Terrell García-Bea, Aintzane Kozlenkov, Alexey Friedman, Allyson K. Moreno, José L. Heshmati, Mitra Golden, Sam A. Kennedy, Pamela J. Takahashi, Nagahide Dietz, David M. Mocci, Giuseppe Gabilondo, Ane M. Hanks, James Umali, Adrienne Callado, Luis F. Gallitano, Amelia L. Neve, Rachael L. Shen, Li Buxbaum, Joseph D. Han, Ming-Hu Nestler, Eric J. Meana, J. Javier Russo, Scott J. González-Maeso, Javier |
author_sort | Kurita, Mitsumasa |
collection | PubMed |
description | 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 show that chronic atypical antipsychotics down-regulate the expression of mGlu2, an effect that is associated with decreased histone acetylation at its promoter in mouse and human frontal cortex. This epigenetic change occurs in concert with a 5-HT(2A) receptor-dependent up-regulation and increased binding of HDAC2 to the mGlu2 promoter. Viral-mediated over-expression of HDAC2 in frontal cortex decreases mGlu2 transcription and its electrophysiological properties, thereby increasing psychosis-like behavior. Conversely, HDAC inhibitors prevent the repressive histone modifications induced at the mGlu2 promoter by atypical antipsychotics, and augment their therapeutic-like effects. These observations support the view of HDAC2 as a promising new target to improve schizophrenia treatment. |
format | Online Article Text |
id | pubmed-3431440 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
record_format | MEDLINE/PubMed |
spelling | pubmed-34314402013-03-01 HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity Kurita, Mitsumasa Holloway, Terrell García-Bea, Aintzane Kozlenkov, Alexey Friedman, Allyson K. Moreno, José L. Heshmati, Mitra Golden, Sam A. Kennedy, Pamela J. Takahashi, Nagahide Dietz, David M. Mocci, Giuseppe Gabilondo, Ane M. Hanks, James Umali, Adrienne Callado, Luis F. Gallitano, Amelia L. Neve, Rachael L. Shen, Li Buxbaum, Joseph D. Han, Ming-Hu Nestler, Eric J. Meana, J. Javier Russo, Scott J. González-Maeso, Javier Nat Neurosci Article 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 show that chronic atypical antipsychotics down-regulate the expression of mGlu2, an effect that is associated with decreased histone acetylation at its promoter in mouse and human frontal cortex. This epigenetic change occurs in concert with a 5-HT(2A) receptor-dependent up-regulation and increased binding of HDAC2 to the mGlu2 promoter. Viral-mediated over-expression of HDAC2 in frontal cortex decreases mGlu2 transcription and its electrophysiological properties, thereby increasing psychosis-like behavior. Conversely, HDAC inhibitors prevent the repressive histone modifications induced at the mGlu2 promoter by atypical antipsychotics, and augment their therapeutic-like effects. These observations support the view of HDAC2 as a promising new target to improve schizophrenia treatment. 2012-08-05 2012-09 /pmc/articles/PMC3431440/ /pubmed/22864611 http://dx.doi.org/10.1038/nn.3181 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Kurita, Mitsumasa Holloway, Terrell García-Bea, Aintzane Kozlenkov, Alexey Friedman, Allyson K. Moreno, José L. Heshmati, Mitra Golden, Sam A. Kennedy, Pamela J. Takahashi, Nagahide Dietz, David M. Mocci, Giuseppe Gabilondo, Ane M. Hanks, James Umali, Adrienne Callado, Luis F. Gallitano, Amelia L. Neve, Rachael L. Shen, Li Buxbaum, Joseph D. Han, Ming-Hu Nestler, Eric J. Meana, J. Javier Russo, Scott J. González-Maeso, Javier HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity |
title | HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity |
title_full | HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity |
title_fullStr | HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity |
title_full_unstemmed | HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity |
title_short | HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity |
title_sort | hdac2 regulates atypical antipsychotic responses through the modulation of mglu2 promoter activity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431440/ https://www.ncbi.nlm.nih.gov/pubmed/22864611 http://dx.doi.org/10.1038/nn.3181 |
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