Department of Neuroscience, Karolinska Institutet, Retzius väg 8, Stockholm S-17177, Sweden.
Department of Neuroscience, Karolinska Institutet, Retzius väg 8, Stockholm S-17177, Sweden.
Neuropharmacology. 2017 Nov;126:242-249. doi: 10.1016/j.neuropharm.2017.09.015. Epub 2017 Sep 13.
Exposure to prenatal insults has been associated with an increased risk for neuropsychiatric disorders, including depression, but the mechanisms are still poorly understood. Persistent alterations of the HPA axis feedback mechanism as well as adult impaired neurogenesis are believed to play a relevant role in the etiology of depression. In addition, growing evidence points at epigenetic reprogramming as a key factor. We have previously shown that prenatal exposure to the synthetic glucocorticoid dexamethasone (DEX) impairs neurogenesis and leads to late onset of depression-like behavior that does not respond to the SSRI antidepressant fluoxetine (FLX). The aims of this study were to assess the effect of DEX prenatal exposure on the morphology of hippocampal granule neurons and on the expression of genes related to plasticity; and to test whether the SNRI antidepressant desipramine (DMI), unlike FLX, could counteract the effect of prenatal-DEX. C57Bl/6 mice were exposed to DEX (0.05 mg/kg/day) in utero and received intra-hippocampal injection of GFP expressing retroviral vector for labeling of newborn granule cells at eleven months. By twelve months, DEX mice showed depression-like behavior associated with decreased neurogenesis and morphological alterations of the newborn granule cells in the dentate gyrus (DG). Furthermore DEX mice displayed altered expression of genes controlling neurogenesis and neuronal morphology, such as Cdkn1c, p16, TrkB, DISC1 and Reelin. Chronic treatment with DMI led to a significant decrease in immobility time in the forced swim test. In addition, DMI restored neurogenesis, neuronal morphology in the DG, as well as the expression of all related genes. Our results suggest that (1) prenatal DEX induces early and persistent reprogramming effects resulting in altered neurogenesis and neuronal morphology; and (2) DMI treatment reverses DEX-induced depression by restoring the expression of genes relevant to neuronal plasticity.
产前暴露于应激原与神经精神疾病风险增加有关，包括抑郁症，但机制仍不清楚。人们认为，HPA 轴反馈机制的持续改变以及成年时神经发生受损在抑郁症的发病机制中起重要作用。此外，越来越多的证据表明表观遗传重编程是一个关键因素。我们之前已经表明，产前暴露于合成糖皮质激素地塞米松（DEX）会损害神经发生，并导致类似抑郁的行为延迟发作，而这种行为对 SSRI 抗抑郁药氟西汀（FLX）没有反应。本研究的目的是评估产前 DEX 暴露对海马颗粒神经元形态和与可塑性相关基因表达的影响；并测试 SNRI 抗抑郁药去甲丙咪嗪（DMI）是否与 FLX 不同，能够抵消产前 DEX 的作用。C57Bl/6 小鼠在子宫内接受 DEX（0.05mg/kg/天）暴露，并在 11 个月时接受 GFP 表达逆转录病毒载体的海马内注射，以标记新生颗粒细胞。在 12 个月时，DEX 小鼠表现出类似抑郁的行为，与新生颗粒细胞在齿状回（DG）中的神经发生减少和形态改变有关。此外，DEX 小鼠显示控制神经发生和神经元形态的基因表达改变，如 Cdkn1c、p16、TrkB、DISC1 和 Reelin。慢性 DMI 治疗导致强迫游泳试验中不动时间显著减少。此外，DMI 恢复了 DG 中的神经发生、神经元形态以及所有相关基因的表达。我们的研究结果表明，（1）产前 DEX 诱导早期和持续的重编程效应，导致神经发生和神经元形态改变；（2）DMI 治疗通过恢复与神经元可塑性相关的基因表达来逆转 DEX 诱导的抑郁。
