Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois Chicago, Chicago, IL, 60612, USA.
Jesse Brown Veterans Affairs Medical Center, Chicago, IL, 60612, USA.
Transl Psychiatry. 2024 Apr 26;14(1):197. doi: 10.1038/s41398-024-02906-y.
Alcohol use and anxiety disorders occur in both males and females, but despite sharing similar presentation and classical symptoms, the prevalence of alcohol use disorder (AUD) is lower in females. While anxiety is a symptom and comorbidity shared by both sexes, the common underlying mechanism that leads to AUD and the subsequent development of anxiety is still understudied. Using a rodent model of adolescent intermittent ethanol (AIE) exposure in both sexes, we investigated the epigenetic mechanism mediated by enhancer of zeste 2 (EZH2), a histone methyltransferase, in regulating both the expression of activity-regulated cytoskeleton-associated protein (Arc) and an anxiety-like phenotype in adulthood. Here, we report that EZH2 protein levels were significantly higher in PKC-δ positive GABAergic neurons in the central nucleus of amygdala (CeA) of adult male and female rats after AIE. Reducing protein and mRNA levels of EZH2 using siRNA infusion in the CeA prevented AIE-induced anxiety-like behavior, increased H3K27me3, decreased H3K27ac at the Arc synaptic activity response element (SARE) site, and restored deficits in Arc mRNA and protein expression in both male and female adult rats. Our data indicate that an EZH2-mediated epigenetic mechanism in the CeA plays an important role in regulating anxiety-like behavior and Arc expression after AIE in both male and female rats in adulthood. This study suggests that EZH2 may serve as a tractable drug target for the treatment of adult psychopathology after adolescent alcohol exposure.
酒精使用和焦虑障碍在男性和女性中均有发生，但尽管表现和典型症状相似，但女性中酒精使用障碍（AUD）的患病率较低。尽管焦虑是两性共有的症状和共病，但导致 AUD 和随后出现焦虑的共同潜在机制仍研究不足。本研究使用雄性和雌性青少年间歇性乙醇（AIE）暴露的啮齿动物模型，研究了增强子结合蛋白 2（EZH2）介导的表观遗传机制，EZH2 是一种组蛋白甲基转移酶，调节活性调节细胞骨架相关蛋白（Arc）的表达和成年后的焦虑样表型。本研究报告，AIE 后雄性和雌性大鼠杏仁中央核（CeA）中 PKC-δ 阳性 GABA 能神经元中 EZH2 蛋白水平显著升高。使用 CeA 中的 siRNA 输注降低 EZH2 的蛋白和 mRNA 水平可预防 AIE 诱导的焦虑样行为，增加 H3K27me3，减少 Arc 突触活性反应元件（SARE）位点的 H3K27ac，并恢复雄性和雌性成年大鼠中 Arc mRNA 和蛋白表达的缺陷。本研究数据表明，CeA 中的 EZH2 介导的表观遗传机制在调节 AIE 后雄性和雌性大鼠的焦虑样行为和 Arc 表达中起重要作用。该研究表明，EZH2 可能作为治疗青少年酒精暴露后成年期精神病理学的一个可行的药物靶点。
