Risperidone Induced DNA Methylation Changes in Dopamine Receptor and Stathmin Genes in Mice Exposed to Social Defeat Stress

Objective@#Understanding complex epigenetic mechanisms is necessary to fully elucidate the effects of antipsychotic drug. This study investigated DNA methylation and mRNA expression levels of dopamine D2 and D1 receptor (Drd2 and Drd1, respectively), nuclear receptor subfamily 3, group C, member 1 (Nr3c1) and stathmin 1 (Stmn1) in brain regions of mice exposed to social defeat stress (SDS) and effects of risperidone on altered methylation and mRNA expression levels induced by SDS. @*Methods@#Following SDS for 10 days, risperidone (0.2 mg/kg) or vehicle was administered to adult mice for 7 days. Brain tissues from the prefrontal cortex (PFC), hippocampus (HIP) and amygdala (AMY) were processed to measure methylation and mRNA levels of Drd2, Drd1, Nr3c1 and Stmn1 using pyrosequencing and real time-polymerase chain reaction. @*Results@#We found altered methylation status of Nr3c1 and Stmn1 in the HIP and AMY of mice exposed to SDS. These changes were reversed by risperidone treatment. In addition, different methylation patterns of Drd2 and Drd1 in the PFC and AMY between defeated and control mice were identified with risperidone treatment. @*Conclusion@#These findings suggest that risperidone can cause epigenetic changes in Drd2, Drd1, Nr3c1 and Stmn1 in defeated mice. These changes could be epigenetic mechanisms underlying antipsychotic efficacy.

Impact of Social Defeat Stress on DNA Methylation in Drd2, Nr3c1, and Stmn1 in Wild-type and Stmn1 Knock-out Mice

Objective@#Epigenetic profiles can be modified by stress. Dopamine receptor D2 (Drd2), glucocorticoid receptor gene (Nr3c1) and Stathmin 1 (Stmn1) genes are all implicated in adaptation to stress. The aim of study is to investigate impact of social defeat on DNA methylation in Drd2, Nr3c1, and Stmn1 in wild-type (WT) and Stmn1 knock-out (KO) mice. @*Methods@#The WT and Stmn1 KO mice were subjected to chronic social defeat. Brain tissues of the prefrontal cortex (PFC), amygdala (AMY) and hippocampus (HIP) were obtained. We measured DNA methylation levels of the Drd2, Nr3c1, and Stmn1 genes in the PFC, AMY, and HIP using pyrosequencing. @*Results@#In WT mice, social defeat stress did not induce any changes in Drd2 methylation, whereas significant hypermethylation occurred in Nr3c1 and Stmn1 in the susceptible and unsusceptible groups, respectively, compared to the control group. The methylation responses in the Stmn1 KO mice differed from those seen in the WT mice, such that hypermethylation was evident in all three genes in the susceptible and unsusceptible groups compared to control group. Comparison of the Stmn1 KO and WT mice revealed the same pattern of hypermethylation for all three genes. @*Conclusion@#Social defeat stress induced different epigenetic modifications in three genes among control, unsusceptible, and susceptible groups of WT and Stmn1 KO mice. In particular, hypermethylation of Nr3c1 in the HIP of the susceptible group, and of Stmn1 in the AMY of the unsusceptible group in WT mice, could serve as epigenetic biomarkers of stress susceptibility and stress resilience, respectively.

Development of the Korea-Polyenvironmental Risk Score for Psychosis

Objective@#Comprehensive understanding of polyenvironmental risk factors for the development of psychosis is important. Based on a review of related evidence, we developed the Korea Polyenvironmental Risk Score (K-PERS) for psychosis. We investigated whether the K-PERS can differentiate patients with schizophrenia spectrum disorders (SSDs) from healthy controls (HCs). @*Methods@#We reviewed existing tools for measuring polyenvironmental risk factors for psychosis, including the Maudsley Environmental Risk Score (ERS), polyenviromic risk score (PERS), and Psychosis Polyrisk Score (PPS). Using odds ratios and relative risks for Western studies and the “population proportion” (PP) of risk factors for Korean data, we developed the K-PERS, and compared the scores thereon between patients with SSDs and HCs. In addition, correlation was performed between the K-PERS and Positive and Negative Syndrome Scale (PANSS). @*Results@#We first constructed the “K-PERS-I,” comprising five factors based on the PPS, and then the “K-PERS-II” comprising six factors based on the ERS. The instruments accurately predicted participants’ status (case vs. control). In addition, the K-PERS-I and -II scores exhibited significant negative correlations with the negative symptom factor score of the PANSS. @*Conclusion@#The K-PERS is the first comprehensive tool developed based on PP data obtained from Korean studies that measures polyenvironmental risk factors for psychosis. Using pilot data, the K-PERS predicted patient status (SSD vs. HC). Further research is warranted to examine the relationship of K-PERS scores with clinical outcomes of psychosis and schizophrenia.