Abstract：
Accumulating evidence suggests that prenatal stress (PNS) increases offspring susceptibility to depression, but the underlying mechanisms remain unclear. We constructed a mouse model of prenatal stress by spatially restraining pregnant mice from 09:00-11:00 daily on Days 5-20 of gestation. In this study, western blot analysis, quantitative real-time PCR (qRT‒PCR), immunofluorescence, immunoprecipitation, chromatin immunoprecipitation (ChIP), and mifepristone rescue assays were used to investigate alterations in the GR/P300-MKP1 and downstream ERK/CREB/TRKB pathways in the brains of prenatally stressed offspring to determine the pathogenesis of the reduced neurogenesis and depression-like behaviors in offspring induced by PNS. We found that prenatal stress leads to reduced hippocampal neurogenesis and depression-like behavior in offspring. Prenatal stress causes high levels of glucocorticoids to enter the fetus and activate the hypothalamic‒pituitary‒adrenal (HPA) axis, resulting in decreased hippocampal glucocorticoid receptor (GR) levels in offspring. Furthermore, the nuclear translocation of GR and P300 (an acetylation modifying enzyme) complex in the hippocampus of PNS offspring increased significantly. This GR/P300 complex upregulates MKP1, which is a negative regulator of the ERK/CREB/TRKB signaling pathway associated with depression. Interestingly, treatment with a GR antagonist (mifepristone, RU486) increased hippocampal GR levels and decreased MKP1 expression, thereby ameliorating abnormal neurogenesis and depression-like behavior in PNS offspring. In conclusion, our study suggested that the regulation of the MKP1 signaling pathway by GR/P300 is involved in depression-like behavior in prenatal stress-exposed offspring and provides new insights and ideas for the fetal hypothesis of mental health.
摘要：
越来越多的证据表明，产前应激（PNS）增加后代对抑郁症的易感性，但潜在的机制仍不清楚。我们通过在妊娠的第5-20天每天09:00-11:00空间限制妊娠小鼠，构建了产前应激的小鼠模型。在这项研究中,蛋白质印迹分析,实时定量PCR(qRT-PCR),免疫荧光，免疫沉淀,染色质免疫沉淀（ChIP），和米非司酮抢救试验用于研究产前应激后代大脑中GR/P300-MKP1和下游ERK/CREB/TRKB通路的变化，以确定PNS诱导的后代神经发生和抑郁样行为减少的发病机理。我们发现，产前应激导致后代海马神经发生减少和抑郁样行为。产前压力导致高水平的糖皮质激素进入胎儿并激活下丘脑-垂体-肾上腺（HPA）轴，导致后代海马糖皮质激素受体（GR）水平降低。此外，PNS后代海马中GR和P300（一种乙酰化修饰酶）复合物的核易位显着增加。该GR/P300复合物上调MKP1，MKP1是与抑郁症相关的ERK/CREB/TRKB信号通路的负调节因子。有趣的是,用GR拮抗剂治疗(米非司酮，RU486)增加海马GR水平，降低MKP1表达，从而改善PNS后代的异常神经发生和抑郁样行为。总之,我们的研究表明,GR/P300对MKP1信号通路的调控参与了产前应激暴露后代的抑郁样行为,为胎儿心理健康假说提供了新的见解和思路.
