Differential brain ADRA2A and ADRA2C gene expression and epigenetic regulation in schizophrenia. Effect of antipsychotic drug treatment

Abstract

Postsynaptic α_2A-adrenoceptor density is enhanced in the dorsolateral prefrontal cortex (DLPFC) of antipsychotic-treated schizophrenia subjects. This alteration might be due to transcriptional activation, and could be regulated by epigenetic mechanisms such as histone posttranslational modifications (PTMs). The aim of this study was to evaluate ADRA2A and ADRA2C gene expression (codifying for α₂-adrenoceptor subtypes), and permissive and repressive histone PTMs at gene promoter regions in the DLPFC of subjects with schizophrenia and matched controls (n = 24 pairs). We studied the effect of antipsychotic (AP) treatment in AP-free (n = 12) and AP-treated (n = 12) subgroups of schizophrenia subjects and in rats acutely and chronically treated with typical and atypical antipsychotics. ADRA2A mRNA expression was selectively upregulated in AP-treated schizophrenia subjects (+93%) whereas ADRA2C mRNA expression was upregulated in all schizophrenia subjects (+53%) regardless of antipsychotic treatment. Acute and chronic clozapine treatment in rats did not alter brain cortex Adra2a mRNA expression but increased Adra2c mRNA expression. Both ADRA2A and ADRA2C promoter regions showed epigenetic modification by histone methylation and acetylation in human DLPFC. The upregulation of ADRA2A expression in AP-treated schizophrenia subjects might be related to observed bivalent chromatin at ADRA2A promoter region in schizophrenia (depicted by increased permissive H3K4me3 and repressive H3K27me3) and could be triggered by the enhanced H4K16ac at ADRA2A promoter. In conclusion, epigenetic predisposition differentially modulated ADRA2A and ADRA2C mRNA expression in DLPFC of schizophrenia subjects.