1. Gene deficiency and pharmacological inhibition of caspase-1 confers resilience to chronic social defeat stress via regulating the stability of surface AMPARs.
- Author
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Li, M-X, Zheng, H-L, Luo, Y, He, J-G, Wang, W, Han, J, Zhang, L, Wang, X, Ni, L, Zhou, H-Y, Hu, Z-L, Wu, P-F, Jin, Y, Long, L-H, Zhang, H, Hu, G, Chen, J-G, and Wang, F
- Subjects
Animals ,Anxiety ,Behavior ,Animal ,Caspase 1 ,Depression ,Disease Models ,Animal ,Hippocampus ,Interleukin-1beta ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Mood Disorders ,Receptors ,Glutamate ,Resilience ,Psychological ,Stress ,Psychological ,Synaptic Transmission ,alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - Abstract
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.
- Published
- 2018