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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.

SUBMITTER: Brocos-Mosquera I

PROVIDER: S-EPMC8688495 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Schizophrenia patients demonstrate variations in response to different therapies that are currently being used for the treatment of disorders, such as augmentation therapy (ECT or mood stabilizer) and combination therapy (with antipsychotics). These therapies are also used to treat schizophrenia patients in Pakistan; however, patients show poor overall response. Therefore, this study was conducted to investigate the association between the patients' response to treatment and the use of antipsychotic agents, with variability in overall response, within different groups of patients. Methods: We conducted a retrospective study that included schizophrenia subjects (N = 200) belonging to different age groups, ethnicities, and regions from different outpatient and inpatient departments in psychiatric institutes located in different cities of Pakistan. These patients were assessed for their response to treatment therapies and categorized into four groups (non-responders (N-R), slow response (S-R), patients with relapse, and completely recovered patients (C-R)) according to their responses. Results: The final analysis included 200 subjects, of which 73.5% were males. Mean age was 34 ± 10 years. Percentage of N-R was 5%, S-R was 42%, patients with relapse were 24%, and C-R was 1.5%. The generalized linear regression model shows a significant association between medication response and age (p = 0.0231), age of onset (p = 0.0086), gender (p = 0.005), and marital status (p = 0.00169). Variability within the medication responses was a result of the treatment regime followed. Antipsychotic agents were significantly associated with the treatment response (p = 0.00258, F = 4.981) of the patients. Significant variation was also observed in the treatment response (p = 0.00128) of the patients that were given augmentation therapy as well as combination therapy. Conclusion: The data suggests proper monitoring of patients' behavior in response to treatment therapies to implement tailored interventions. Despite several genetic studies supporting the heritability of schizophrenia, an insignificant association between characteristic features and family history might have been due to the limited sample size, suggesting collaborative work with massive sample sizes.

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

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