Mol Psychiatry:环境为何会引发抑郁行为
生物通 · 2017/05/21
来自华中科技大学的研究人员揭示了抑郁症发生的新机制:炎症信号分子caspase-1通过调控谷氨酸受体膜稳定性,将环境应激与抑郁样行为相偶联,从新的角度阐明了社会压力是如何导致抑郁样行为的。


本文转载自 生物通

抑郁症是最常见的精神障碍性疾病之一,具有高发病率、高复发率和高自杀率等特点,已成为严重危害人类生命与健康的重大公共卫生问题。但目前抑郁症发病机制尚未阐明,临床上常用的针对单胺类神经递质系统研发的抗抑郁药,起效慢且疗效有限。

近期来自华中科技大学的研究人员发表了题为“Gene deficiency and pharmacological inhibition of caspase-1 confers resilience to chronic social defeat stress via regulating the stability of surface AMPARs”的文章,揭示了抑郁症发生的新机制:炎症信号分子caspase-1通过调控谷氨酸受体膜稳定性,将环境应激与抑郁样行为相偶联,从新的角度阐明了社会压力是如何导致抑郁样行为的

这一研究成果公布在神经精神病学顶尖杂志Molecular Psychiatry(年最高影响因子15.1)上,文章的通讯作者是华中科技大学基础医学院陈建国教授与王芳教授,第一作者是博士生李明星。

以往的研究发现抑郁症患者血液中炎症标记物水平增加,但这些异常增加的炎症因子与抑郁症的发生是否有因果关系?它们又是如何引起抑郁症发生发展的?

caspase-1是主要的炎症相关caspases家族成员,在调控炎症反应方面发挥重要作用。在这篇文章中,研究人员采用基因敲除、行为学、电生理记录和分子生物学等技术手段,通过建立慢性社会挫败性应激(CSDS)等小鼠抑郁模型,发现应激可增加小鼠海马脑区caspase-1水平,敲除caspase-1基因或外源性给予选择性caspase-1抑制剂可逆转小鼠抑郁样行为,过表达caspase-1基因或外源性给予IL-1β可引起小鼠抑郁样行为。

但与传统炎症反应机制不同,这项研究发现caspase-1/IL-1β信号通路异常激活通过减少海马区AMPA受体的膜表达,损伤突触功能,从而表明caspase-1活性增加介导的海马区突触功能异常是抑郁症发生的重要环节。这一发现将抑郁症“炎症假说”和“神经可塑性假说”相关联,揭示了抑郁症发生的新机制,并为抗抑郁药的研发提供了新靶点。

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  • Gene deficiency and pharmacological inhibition of caspase-1 confers resilience to chronic social defeat stress via regulating the stability of surface AMPARs

    Both inflammatory processes and glutamatergic systems have been implicated in the pathophysiology of mood-related disorders. However, the role of caspase-1, a classic inflammatory caspase, in behavioral responses to chronic stress remains largely unknown. To address this issue, we examined the effects and underlying mechanisms of caspase-1 on preclinical murine models of depression. We found that loss of caspase-1 expression in Caspase-1−/− knockout mice alleviated chronic stress-induced depression-like behaviors, whereas overexpression of caspase-1 in the hippocampus of wild-type (WT) mice was sufficient to induce depression- and anxiety-like behaviors. Furthermore, chronic stress reduced glutamatergic neurotransmission and decreased surface expression of glutamate receptors in hippocampal pyramidal neurons of WT mice, but not Caspase-1−/− mice. Importantly, pharmacological inhibition of caspase-1-interleukin-1β (IL-1β) signaling pathway prevented the depression-like behaviors and the decrease in surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in stressed WT mice. Finally, the effects of chronic stress on both depression- and anxiety-like behaviors can be mimicked by exogenous intracerebroventricular (i.c.v.) administration of IL-1β in both WT and Caspase-1−/− mice. Taken together, our findings demonstrate that an increase in the caspase-1/IL-1β axis facilitates AMPAR internalization in the hippocampus, which dysregulates glutamatergic synaptic transmission, eventually resulting in depression-like behaviors. These results may represent an endophenotype for chronic stress-induced depression.

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