Abstract
Postsynaptic α2A-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.
Highlights
Schizophrenia is a chronic and disabling disease that affects around 1% of the world population [1]
Demographic and methodological variables contributing to ADRA2A and ADRA2C mRNA expression in human dorsolateral prefrontal cortex (DLPFC) First, multiple regression analysis of data from control subjects was performed in order to study the contribution of nominal predictor variables and continuous predictor variables to corrected ADRA2A and ADRA2C mRNA expression
The analysis revealed that corrected ADRA2A mRNA expression was significantly influenced by RNA integrity number (RIN) of the samples (β = −0.6, p = 0.007), regardless of sex and age of the subjects and PMD and ST
Summary
Schizophrenia is a chronic and disabling disease that affects around 1% of the world population [1]. Among the three α2-adrenoceptor subtypes (α2A, α2B, and α2C), α2A- and α2Cadrenoceptors show the broadest distribution in central nervous system and they could be relevant in mental disorders as schizophrenia due to their specific role in memory and cognition [3]. Presynaptically located α2-adrenoceptors might affect neuropsychiatric symptoms due to their effect on neurotransmitter feedback and regulation, whereas postsynaptic α2-adrenoceptors in DLPFC (mainly α2A-adrenoceptor subtype) may be critical in the regulation of cognitive functions as working memory [6]. We recently reported postsynaptic α2A-adrenoceptor subtype upregulation in schizophrenia subjects [9]. This finding was specific for those schizophrenia subjects that were under antipsychotic treatment
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