2017年4月18日, 國際學術權威刊物自然出版集團旗下子刊、神經精神病學頂尖雜誌《Molecular Psychiatry》線上發表了華中科技大學基礎醫學院陳建國教授團隊關於抑鬱症發病機制的研究論文, 論文題為“Gene deficiency and pharmacological inhibition of caspase-1 confers resilience to chronic social defeat stress via regulating the stability of surface AMPARs”。 研究揭示了抑鬱症發生的新機制——炎症信號分子caspase-1通過調控谷氨酸受體膜穩定性, 將環境應激與抑鬱樣行為相偶聯, 從新的角度闡明了社會壓力是如何導致抑鬱樣行為的。 創新研究院/基礎醫學院博士生李明星為第一作者, 指導老師陳建國教授和王芳教授作為通訊作者。
抑鬱症是最常見的精神障礙性疾病之一,
以往的研究發現抑鬱症患者血液中炎症標記物水準增加, 但這些異常增加的炎症因數與抑鬱症的發生是否有因果關係?它們又是如何引起抑鬱症發生發展的?caspase-1是主要的炎症相關caspases家族成員, 在調控炎症反應方面發揮重要作用。 該研究採用基因敲除、行為學、電生理記錄和分子生物學等技術手段,
原文連結:
原文摘要:
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, wheras 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 andCaspase-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.