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

Nature Neuroscience volume 15, pages 1245–1254 (2012)Cite this article

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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-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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Figure 1: Decreased acetylation of histone H3 (H3ac) at the mGlu2 promoter by chronic treatment with atypical antipsychotic drugs in mouse frontal cortex.
Figure 2: Decreased acetylation of histone H3 (H3ac) at the mGlu2 promoter in prefrontal cortex of treated, but not untreated, subjects with schizophrenia.
Figure 3: 5-HT2A-dependent increased expression of HDAC2 in frontal cortex by chronic atypical antipsychotics.
Figure 4: HDAC2 binds to the mGlu2 promoter and represses its function.
Figure 5: HSV-HDAC2 in frontal cortex decreases mGlu2-dependent behavioral function.
Figure 6: Chronic treatment with SAHA prevents the repressive histone modifications induced at the mGlu2 promoter by chronic clozapine.

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Acknowledgements

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.

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Author notes

  1. Mitsumasa Kurita and Terrell Holloway: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA

    Mitsumasa Kurita, Terrell Holloway, Aintzane García-Bea, Alexey Kozlenkov, José L Moreno, Mitra Heshmati, Nagahide Takahashi, Giuseppe Mocci, James Hanks, Adrienne Umali, Joseph D Buxbaum, Eric J Nestler & Javier González-Maeso

  2. Department of Pharmacology, University of the Basque Country (UPV/EHU), Leioa, Spain

    Aintzane García-Bea, Ane M Gabilondo, Luis F Callado & J Javier Meana

  3. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Leioa, Spain

    Aintzane García-Bea, Ane M Gabilondo, Luis F Callado & J Javier Meana

  4. Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York, USA

    Allyson K Friedman, Ming-Hu Han & Eric J Nestler

  5. Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA

    Sam A Golden, Pamela J Kennedy, David M Dietz, Li Shen, Joseph D Buxbaum, Ming-Hu Han, Eric J Nestler & Scott J Russo

  6. Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA

    Amelia L Gallitano

  7. Department of Psychiatry, University of Arizona College of Medicine, Phoenix, Arizona, USA

    Amelia L Gallitano

  8. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Rachael L Neve

  9. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA

    Joseph D Buxbaum

  10. Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, USA

    Joseph D Buxbaum, Ming-Hu Han, Eric J Nestler, Scott J Russo & Javier González-Maeso

  11. Department of Neurology, Mount Sinai School of Medicine, New York, New York, USA

    Javier González-Maeso

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  1. Mitsumasa Kurita
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Contributions

M.K. and J.G.-M. designed experiments, analyzed data and wrote the manuscript. M.K. performed experiments. J.G.-M. supervised the research. T.H. performed behavior experiments. A.G.-B. performed experiments in post-mortem schizophrenia-affected brain. A.K. assisted with cloning and performed promoter assay experiments. J.L.M. performed radioligand binding experiments. M.H. assisted with ChIP and DNA methylation assays. G.M., A.M.G., J.H., A.U. and A.L.G. assisted with experiments. R.L.N. performed viral packaging. L.S. performed biostatistical analyses. L.F.C. and J.J.M. obtained and classified post-mortem human brain samples. S.A.G., supervised by S.J.R., helped with stereotaxic surgery. P.J.K. and D.M.D., supervised by E.J.N., helped with viral overexpression. A.K.F., supervised by M.-H.H., performed electrophysiological studies. N.T., supervised by J.D.B., helped with prepulse inhibition test. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Javier González-Maeso.

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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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