Regulation of histone deacetylases (HDACs) and modulation of metabotropic glutamate mGlu2 receptor promoter activity by atypical antipsychotics in postmortem brain of schizophrenic subjects.

AM Gabilondo1, A García-Bea1, P Miranda-Azpiazu1, K Mitsumasa2, LF Callado1, J Gonzalez-Maeso3, JJ Meana1. 1University of the Basque Country (UPV/EHU), Department of Pharmacology and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM); E-48940, Leioa, Bizkaia, Spain, 2Mount Sinai School of Medicine, Department of Psychiatry; New York, NY 10029, USA, 3Mount Sinai School of Medicine, Departments of Psychiatry, Neurology, and Friedman Brain Institute, ; New York, NY 10029, USA

Epigenetic changes seem to play a role in the etiology and/or treatment of schizophrenia. Clinical data show that HDAC inhibitors, when given in combination with atypical antipsychotics, are efficacious in schizophrenia patients [1]. Also, multiple lines of evidence associate schizophrenia with dysfunction of glutamatergic transmission. In human frontal cortex, metabotropic glutamate mGlu2 receptors (mGlu2) form functional complexes with serotonin 5HT2A receptors (5HT2A) [2], being 5HT2A a pharmacological target of atypical antipsychotics. Drugs that activate mGlu2 lead to a lower 5HT2A-dependent response, and recent preclinical and clinical studies suggest that these glutamatergic drugs could represent new antipsychotic medications [3].

In this study, the protein expression of HDAC1, HDAC2, HDAC4 and mGlu2; the mRNA expression of HDAC1, HDAC2 and mGlu2; and acetylation of histone H3 associated with the promoter regions of mGlu2, mGlu3, 5HT2A and 5HT2C genes were evaluated in prefrontal cortex (Brodmann´s area 9) from antipsychotic-free (AP-free, n=9-11) and antipsychotic-treated (AP-treated, n=8) schizophrenic subjects and control subjects individually matched for age, gender and post-mortem delay. For that, western blot, quantitative real-time PCR, and chromatin immunoprecipitation (ChIP) assays were performed.

In AP-treated schizophrenics, protein expression of HDAC2 was up-regulated (129±15% vs matched controls; t-test p<0.05) without significant changes in HDAC2 (mRNA), HDAC1 (mRNA and protein), and HDAC4 (protein) expression. This antipsychotic-dependent over-expression of HDAC2 occurred in concert with a selective decrease of H3 histone acetylation at the mGlu2 promoter (73±9% vs matched controls; t-test p<0.05) and with a lower expression of mGlu2 (mRNA: 66±10% vs matched controls, t-test p<0.05; protein: 70±13% vs matched controls, t-test p<0.05). In AP-free schizophrenics no significant change in any of the studied parameters was observed with respect to their matched controls.

These results suggest that the selective dysregulation of HDAC2 and the lower mGlu2 expression in schizophrenic subjects are consequences of the antipsychotic treatment instead of biochemical markers of schizophrenia. The repressive effect of atypical antipsychotics on mGlu2 expression could lead to a lower inhibitory effect of these receptors on 5HT2A-dependent responses, which could be related with the lack of therapeutic response that occurs in some patients or with some negative effects that these drugs can induce on cognitive processes. Thus, these results support the development and testing of HDAC2 selective inhibitors as adjuvant drugs for the treatment of schizophrenia.

Supported by MICINN (SAF2009-084609 to J.J.M.), the Basque Government (IT-199-07 to J.J.M. and S-PE11UN069 to A.M.G.), NIH (R01 MH084894 to J.G.M.), and Dainippon Sumitomo Pharma (J.G.M.). A.G.-B. holds a predoctoral fellowship from the Basque Government.

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[3] Patil, S.T. et al. (2007) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat. Med. 13, 1102–1107.