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.

中文翻译：

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caspase-1的基因缺陷和药理抑制作用通过调节表面AMPAR的稳定性赋予了抵抗慢性社交衰竭压力的能力。

炎症过程和谷氨酸能系统均与情绪相关疾病的病理生理有关。但是，caspase-1（一种经典的炎症性caspase）在对慢性应激的行为反应中的作用仍然未知。为了解决这个问题，我们研究了caspase-1在临床前抑郁鼠模型中的作用及其潜在机制。我们发现Caspase-1中caspase-1表达的丧失^-/-基因敲除小鼠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的过表达足以诱导抑郁症和焦虑样行为。此外，慢性应激降低了野生型小鼠海马锥体神经元的谷氨酸能神经传递，并降低了谷氨酸受体的表面表达，但不降低Caspase-1 ^-/-。老鼠。重要的是，药理作用抑制caspase-1-interleukin-1β（IL-1β）信号通路可防止抑郁症样行为和α-氨基-3-羟基-5-甲基-5-异-4-咪唑丙酸受体表面表达的降低（ WT小鼠中的AMPARs）。最后，慢性应激对抑郁和焦虑样行为的影响可以通过在WT和Caspase-1 ^-/-小鼠中外源性脑室内（icv）给予IL-1β来模拟。两者合计，我们的发现表明，caspase-1 /IL-1β轴的增加促进了海马中AMPAR的内在化，从而使谷氨酸能突触传递失调，最终导致了抑郁样行为。这些结果可能代表了慢性应激引起的抑郁症的内表型。