Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors
Social defeat (SD) stress induces social avoidance and anxiety-like phenotypes. Amygdala is recognized as an emotion-related brain region such as fear, aversion and anxiety. It is conceivable to hypothesize that activation of amygdala is involved in SD-dependent behavioral defects. SD model was established using C57BL/6J mice that were physically defeated by different CD-1 mice for 10 days. Stressed mice exhibited decreased social interaction level in social interaction test and significant anxiety-like behaviors in elevated plus maze and open field tests. Meanwhile, a higher phosphorylation of PKA and CREB with a mutually linear correlation, and increased Fos labeled cells in the basolateral amygdala (BLA) were observed. Activation of PKA in the BLA by 8-Br-cAMP, a PKA activitor, significantly upregulated pCREB and Fos expression. To address the role of PKA activation on SD stress-induced social avoidance and anxiety-like behaviors, 8-Br-cAMP or H-89, a PKA inhibitor, was continuously administered into the bilateral BLA by a micro-osmotic pump system during the 10-day SD period. Neither H-89 nor 8-Br-cAMP affected the social behavior. Differently, 8-Br-cAMP significantly relieved anxiety-like behaviors in both general and moderate SD protocols. H-89 per se did not have anxiogenic effect in naïve mice, but aggravated moderate SD stress-induced anxiety-like behaviors. The antidepressant clomipramine reduced SD-induced anxiety and up-regulated pPKA level in the BLA. These results suggest that SD-driven PKA activation in the basolateral amygdala is actually a compensatory rather than pathogenic response in the homeostasis, and modulating amygdaloid PKA may exhibit potency in the therapy of social derived disorders.