Hippocampal Salt-Inducible Kinase 2 Plays a Role in Depression via the CREB-Regulated Transcription Coactivator 1-cAMP Response Element Binding-Brain-Derived Neurotrophic Factor Pathway
Hippocampal Salt-Inducible Kinase 2 Plays a Role in Depression via the CREB-Regulated Transcription Coactivator 1-cAMP Response Element Binding-Brain-Derived Neurotrophic Factor Pathway
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DOI：
10.1016/j.biopsych.2018.10.004
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发表时间：
2019-04-15
影响因子：
10.6
通讯作者：
Li, Jun-Xu
中科院分区：
文献类型：
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作者：
Jiang, Bo;Wang, Hao;Li, Jun-Xu
背景：开发超越单胺能系统的新药理学靶点现在是寻找治疗抑郁症新方法的流行策略。盐诱导激酶（SIK）是一种通过磷酸化调控环腺苷单磷酸反应元件结合蛋白（CREB）调控的转录共激活因子（CRTC）核易位的激酶。在这里，我们假设中枢SIK-CRTC系统的功能障碍可能与抑郁症的发病机制有关。方法：本研究采用慢性社会失败应激（CSDS）和慢性不可预测轻度应激（CUMS）抑郁症模型、各种行为测试、病毒介导的基因转移、Western blotting、共免疫沉淀、定量实时逆转录聚合酶链反应和免疫组织化学（体内研究n = 10，体外研究n = 5）。结果：CSDS和CUMS均显著增加海马SIK2的表达，减少CRTC1核易位和CRTC1与CREB在海马中的结合。幼稚小鼠海马SIK2基因过表达模拟慢性应激，诱导强迫游泳试验、悬尾试验、蔗糖偏好试验和社会互动试验中的抑郁样行为，减少海马脑源性神经营养因子信号级联和神经发生。相比之下，基因敲低和敲除海马SIK2可以预防CSDS和CUMS，并通过下游的crtc1 - creb -脑源性神经营养因子通路发挥显着的抗抑郁样作用。此外，氟西汀、文拉法辛和米氮平均能显著恢复CSDS和CUMS对海马SIK2-CRTC1通路的影响，这是其抗抑郁作用所必需的。结论：海马SIK2- crtc1通路参与抑郁症的发病机制，海马SIK2可能是开发抗抑郁药的新靶点。
BACKGROUND: Developing novel pharmacological targets beyond monoaminergic systems is now a popular strategy for finding new ways to treat depression. Salt-inducible kinase (SIK) is a kinase that regulates the nuclear translocation of cyclic adenosine monophosphate response element binding protein (CREB)-regulated transcription coactivator (CRTC) by phosphorylation. Here, we hypothesize that dysfunction of the central SIK-CRTC system may contribute to the pathogenesis of depression.METHODS: Chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression, various behavioral tests, viral-mediated gene transfer, Western blotting, coimmunoprecipitation, quantitative real-time reverse transcription polymerase chain reaction, and immunohistochemistry were used in this study (for in vivo studies, n = 10; for in vitro studies, n = 5).RESULTS: Both CSDS and CUMS markedly increased the expression of hippocampal SIK2, which reduced CRTC1 nuclear translocation and binding of CRTC1 and CREB in the hippocampus. Genetic overexpression of hippocampal SIK2 in naive mice simulated chronic stress, inducing depressive-like behaviors in the forced swim test, tail suspension test, sucrose preference test, and social interaction test, as well as decreasing the brain-derived neurotrophic factor signaling cascade and neurogenesis in the hippocampus. In contrast, genetic knockdown and knockout of hippocampal SIK2 protected against CSDS and CUMS, exerting significant antidepressant-like effects that were mediated via the downstream CRTC1-CREB-brain-derived neurotrophic factor pathway. Moreover, fluoxetine, venlafaxine, and mirtazapine all significantly restored the effects of CSDS and CUMS on the hippocampal SIK2-CRTC1 pathway, which was necessary for their antidepressant actions.CONCLUSIONS: The hippocampal SIK2-CRTC1 pathway is involved in the pathogenesis of depression, and hippocampal SIK2 could be a novel target for the development of antidepressants.