Gene deficiency and pharmacological inhibition of caspase-1 confers resilience to chronic social defeat stress via regulating the stability of surface AMPARs.
Gene deficiency and pharmacological inhibition of caspase-1 confers resilience to chronic social defeat stress via regulating the stability of surface AMPARs.
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caspase-1 的基因缺陷和药理抑制通过调节表面 AMPAR 的稳定性赋予对慢性社会失败压力的恢复能力
DOI：
10.1038/mp.2017.76
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发表时间：
2018-03
影响因子：
11
通讯作者：
Wang F
中科院分区：
文献类型：
--
作者：
Li MX;Zheng HL;Luo Y;He JG;Wang W;Han J;Zhang L;Wang X;Ni L;Zhou HY;Hu ZL;Wu PF;Jin Y;Long LH;Zhang H;Hu G;Chen JG;Wang F
炎症过程和代谢能系统都与情绪相关疾病的病理生理学有关。然而，caspase-1，一种经典的炎症caspase，在慢性应激的行为反应中的作用仍然很大程度上未知。为了解决这个问题，我们研究了caspase-1对临床前抑郁症小鼠模型的影响和潜在机制。我们发现，Caspase-1−/−敲除小鼠中caspase-1表达的缺失减轻了慢性应激诱导的抑郁样行为，而野生型（WT）小鼠海马中caspase-1的过度表达足以诱导抑郁和焦虑样行为。此外，慢性应激减少了WT小鼠海马锥体神经元的谷氨酸能神经传递和谷氨酸受体的表面表达，但没有Caspase-1−/−小鼠。重要的是，药物抑制caspase-1-白细胞介素-1 β（IL-1β）信号通路可防止应激WT小鼠的抑郁样行为和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）表面表达的减少。最后，慢性应激对抑郁和焦虑样行为的影响可以通过外源性脑室内（i. c. v.）在WT和Caspase-1−/−小鼠中给予IL-1β。综上所述，我们的研究结果表明，caspase-1/IL-1β轴的增加促进海马中的AMPAR内化，这使海马能突触传递失调，最终导致抑郁样行为。这些结果可能代表了慢性应激诱导的抑郁症的内在表型。
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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DOI：
10.1073/pnas.1203930109
发表时间：
2012-05-01
影响因子：
11.1
作者：
Feng, Zhaohui;Liu, Lianxin;Hu, Wenwei
通讯作者：
Hu, Wenwei
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.7
作者：
Anacker, Christoph;Zunszain, Patricia A.;Carvalho, Livia A.;Pariante, Carmine M.
通讯作者：
Pariante, Carmine M.
影响因子：
5.3
作者：
Bilbo, SD;Biedenkapp, JC;Maier, SF
通讯作者：
Maier, SF
影响因子：
4.8
作者：
Chourbaji, S.;Vogt, M. A.;Gass, P.
通讯作者：
Gass, P.