Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan; Fishberg Department of Neuroscience and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.
Psychoneuroendocrinology. 2020 Oct;120:104800. doi: 10.1016/j.psyneuen.2020.104800. Epub 2020 Jul 11.
Prior studies suggest that individual differences in stress responses contribute to the pathogenesis of neuropsychiatric disorders. In the present study, we investigated the role of small ubiquitin-like modifier (SUMO) E3 ligase protein inhibitor of activated STAT1 (PIAS1) in mediating stress responses to chronic social defeat stress (CSDS). We found that mRNA and protein levels of PIAS 1 were decreased in the hippocampus of high-susceptibility (HS) mice but not in low-susceptibility (LS) mice after CSDS. Local overexpression of PIAS1 in the hippocampus followed by CSDS exposure promoted stress resilience by attenuating social avoidance and improving anxiety-like behaviors. Viral-mediated gene transfer to generate a conditional knockdown of PIAS1 in the hippocampus promoted social avoidance and stress vulnerability after subthreshold microdefeat. HS mice displayed decreased levels of glucocorticoid receptor (GR) expression, and GR SUMOylation in the hippocampus was associated with stress vulnerability. Furthermore, cytokine/chemokine levels were changed predominantly in the hippocampus of HS mice. These results suggest that hippocampal PIAS1 plays a role in the regulation of stress susceptibility by post-translational modification of GRs.
先前的研究表明，应激反应的个体差异导致神经精神疾病的发病机制。在本研究中，我们研究了小泛素样修饰物（SUMO）E3 连接酶蛋白激活 STAT1 的抑制剂（PIAS1）在介导慢性社会挫败应激（CSDS）的应激反应中的作用。我们发现，在 CSDS 后，高易感性（HS）小鼠的海马体中 PIAS1 的 mRNA 和蛋白水平降低，但低易感性（LS）小鼠中没有降低。CSDS 暴露后，海马体中 PIAS1 的局部过表达促进了应激适应，减轻了社交回避，并改善了焦虑样行为。病毒介导的基因转移，使海马体中的 PIAS1 条件性敲低，会在阈下微挫败后促进社交回避和应激易感性。HS 小鼠显示出糖皮质激素受体（GR）表达水平降低，并且海马体中的 GR SUMO 化与应激易感性相关。此外，细胞因子/趋化因子水平主要在 HS 小鼠的海马体中发生改变。这些结果表明，海马体中的 PIAS1 通过 GR 的翻译后修饰在调节应激易感性方面发挥作用。
