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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.

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-1? (IL-1?) signaling pathway prevented the depression-like behaviors and the decrease in surface expression of ?-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-1? in both WT and Caspase-1^-/- mice. Taken together, our findings demonstrate that an increase in the caspase-1/IL-1? 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.

SUBMITTER: Li MX

PROVIDER: S-EPMC5822452 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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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.

Li M-X MX Zheng H-L HL Luo Y Y He J-G JG Wang W W Han J J Zhang L L Wang X X Ni L L Zhou H-Y HY Hu Z-L ZL Wu P-F PF Jin Y Y Long L-H LH Zhang H H Hu G G Chen J-G JG Wang F F

Molecular psychiatry 20170418 3

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<sup>-/-</sup> knockout mice alleviated chronic stress-indu ...[more]

PMID: 28416811

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Project description:Dysregulation of innate immune responses has frequently been reported in stress-associated psychiatric disorders such as major depression. In mice, enhanced circulating cytokine levels as well as altered innate immune cell numbers have been found after stress exposure. In addition, stress-induced recruitment of peripheral monocytes to the brain has been shown to promote anxiety-like behavior. However, it is yet unclear whether specific differences in the innate immune system are associated with stress susceptibility or resilience in mice. Utilizing chronic social defeat, a model of depression and stress vulnerability, we characterized peripheral and brain-invading myeloid cells in stress-susceptible and resilient animals. In all defeated animals, we found reduced percentages of CD11c+ dendritic cells (DCs) by flow cytometry in the spleen when compared to non-defeated controls. Exclusively in susceptible mice conventional DCs of the spleen showed up-regulated expression of MHC class II and co-stimulatory CD80 molecules pointing toward an enhanced maturation phenotype of these cells. Susceptible, but not resilient animals further exhibited an increase in inflammatory Ly6Chi monocytes and higher numbers of spleen-derived CD11b+ cells that produced the proinflammatory cytokine tumor necrosis factor (TNF) upon lipopolysaccharide (LPS) stimulation. Increased percentages of peripheral CD45hi CD11b+ cells immigrated into the brain of defeated mice, regardless of resilience or susceptibility. However, cellular infiltrates in the brain of susceptible mice contained higher percentages of CC chemokine receptor 2 (CCR2+) Ly6Chi monocytes representing an inflammatory phenotype. Thus, we defined specific stress-related immune signatures involving conventional DCs and inflammatory Ly6Chi monocytes in susceptible and resilient mice. Together, our findings suggest an impact of the innate immune system in vulnerability to stress-related disorders such as major depression.

Dataset Information

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

Publications

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

Similar Datasets

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