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 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-HT2A 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.

HDAC1 links early life stress to schizophrenia-like phenotypes

“…The emerging picture suggests that mainly class I HDACs might be suitable targets to treat brain diseases (12,14). HDAC inhibitors are also discussed as novel targets to treat schizophrenia (15)(16)(17). In fact, valproate given in combination with atypical antipsychotics shows beneficial effects in preclinical (18) and clinical (19) studies.…”

L -acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors

“…Identification of the epigenetic mechanisms that integrate a better response to antidepressants with pharmacological modulation of mGlu2 function will help in discovering more effective treatment to improve the clinical efficacy of the common antidepressant drugs. The importance of histone acetylation in the regulation of the mGlu2 receptor is also strengthened by the recent finding that chronic treatment with atypical antipsychotics down-regulated the expression of mGlu2 receptors in the mouse and human prefrontal cortex by increasing the binding of HDAC2 to the Grm2 promoter (39).…”

Repressive Epigenetic Changes at themGlu2Promoter in Frontal Cortex of 5-HT2AKnockout Mice

“…The mouse Egr1 fragment was digested with EcoRI and XhoI, the FLAG fragment was digested with BamHI and EcoRI from pcDNA3.1-FLAG-HDAC2 (Kurita et al, 2012), and these two fragments were simultaneously subcloned into the BamH1 and XhoI sites of pcDNA3.1. For HSV-FLAG-Egr1, the FLAG-Egr1 fragment was digested from pcDNA3.1-FLAG-Egr1 (see cloning above) and subcloned into the BamH1 and XhoI sites of the bicistronic p10051 HSV plasmid expressing green fluorescent protein (GFP) under the control of the CMV promoter (Kurita et al, 2012). The pcDNA3.1-c-Myc-5HT2A plasmid and the mGlu2 promoter construct have been previously described (Kurita et al, 2012;Moreno et al, 2012).…”

“…Previous findings convincingly demonstrate a functional interaction between 5-HT 2A and metabotropic glutamate 2 (mGlu2) receptors in vitro and in rodent models. Thus, drugs that activate the mGlu2 modulate the cellular (Zhai et al, 2003;Benneyworth et al, 2007;Gonzalez-Maeso et al, 2008;Moreno et al, 2011a), electrophysiological Fribourg et al, 2011;Kurita et al, 2012), and behavioral (Gewirtz and Marek, 2000;Benneyworth et al, 2007;Moreno et al, 2011aMoreno et al, , 2012 responses that require expression of the 5-HT 2A receptor in cortical neurons. Of interest, we previously reported that 5-HT 2A -KO mice show reduced cortical expression of mGlu2 mRNA (Gonzalez-Maeso et al, 2008), which further supports the cross-modulation of a diverse array of functions between 5-HT 2A and mGlu2 receptors.…”