Prenatal stress (PRS) had a long-term adverse effect on motor behaviors. Corticostriatal synaptic plasticity, a cellular basis for motor controlling, has been proven to participate in the pathogenesis of many behavior disorders. Based on the reports about the involvement of epigenetic DNA alterations in PRS-induced long-term effects, this research investigated the influence of PRS on the development and maturation of corticostriatal synaptic plasticity and related behaviors and explored the underlying epigenetic mechanism. Subjects were male offspring of dams that were exposed to stress three times per day from the 10th day of pregnancy until delivery. The development and maturation of plasticity at corticostriatal synapses, dopamine signaling, behavioral habituation, and DNA methylation were examined and analyzed. Control mice expressed long-term potentiation (LTP) at corticostriatal synapses during postnatal days (PD) 12-14 and produced long-term depression (LTD) during PD 20-60. However, PRS mice exhibited sustained LTP during PD 12-60. The treatment with dopamine 2 receptor (D2R) agonist quinpirole recovered striatal LTD and improved the impaired behavioral habituation in PD 45 adult PRS mice. Additionally, adult PRS mice showed reduced D2R, excess DNA methyltransferase 1 (DNMT1), increased binding of DNMT1 to D2R promoter, and hypermethylation at D2R promoter in the striatum. The DNMT1 inhibitor 5-aza-deoxycytidine restored striatal synaptic plasticity and improved behavioral habituation in adult PRS mice via D2R-mediated dopamine signaling. DNMT1-associated D2R hypermethylation is responsible for altering the maturation of plasticity at corticostriatal synapses and impairing the behavioral habituation in PRS mice.

中文翻译：

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产前压力通过小鼠多巴胺 D2 受体的表观遗传修饰导致皮质纹状体突触可塑性成熟度的改变和相关行为障碍。


产前应激（PRS）对运动行为有长期的不利影响。皮质纹状体突触可塑性是运动控制的细胞基础，已被证明参与许多行为障碍的发病机制。本研究基于表观遗传DNA改变参与PRS引起的长期效应的报道，研究了PRS对皮质纹状体突触可塑性发育和成熟及相关行为的影响，并探讨了其潜在的表观遗传机制。受试者是水坝的雄性后代，从怀孕第 10 天到分娩，每天暴露在压力下 3 次。对皮质纹状体突触可塑性的发育和成熟、多巴胺信号传导、行为习惯和 DNA 甲基化进行了检查和分析。对照小鼠在出生后 12-14 天 (PD) 期间皮质纹状体突触表达长时程增强 (LTP)，并在 PD 20-60 天期间产生长期抑制 (LTD)。然而，PRS 小鼠在 PD 12-60 期间表现出持续的 LTP。使用多巴胺 2 受体 (D2R) 激动剂喹吡罗治疗可恢复纹状体 LTD，并改善 PD 45 成年 PRS 小鼠受损的行为习惯。此外，成年 PRS 小鼠表现出 D2R 减少、DNA 甲基转移酶 1 (DNMT1) 过量、DNMT1 与 D2R 启动子的结合增加以及纹状体中 D2R 启动子的高甲基化。 DNMT1 抑制剂 5-氮杂-脱氧胞苷通过 D2R 介导的多巴胺信号传导恢复了成年 PRS 小鼠的纹状体突触可塑性并改善了行为习惯。 DNMT1 相关的 D2R 高甲基化负责改变皮质纹状体突触可塑性的成熟并损害 PRS 小鼠的行为习惯。