Neuron stem cell NLRP6 sustains hippocampal neurogenesis to resist stress-induced depression

Neurogenesis decline in hippocampal dentate gyrus(DG)participates in stress-induced depressive-like behaviors,but the underlying mechanism remains poorly understood.Here,we observed low-expression of NOD-like receptor family pyrin domain containing 6(NLRP6)in hippocampus of stress-stimulated mice,being consistent with high corticosterone level.NLRP6 was found to be abundantly expressed in neural stem cells(NSCs)of DG.Both Nlrp6 knockout(Nlrp6^(-/-))and NSCconditional Nlrp6 knockout(Nlrp6CKO)mice were susceptible to stress,being more likely to develop depressive-like behaviors.Interestingly,NLRP6 was required for NSC proliferation in sustaining hippocampal neurogenesis and reinforcing stress resilience during growing up.Nlrp6 deficiency promoted esophageal cancer-related gene 4(ECRG4)expression and caused mitochondrial dysfunction.Corticosterone as a stress factor significantly down-regulated NLRP6 expression,damaged mitochondrial function and suppressed cell proliferation in NSCs,which were blocked by Nlrp6 overexpression.ECRG4 knockdown reversed corticosterone-induced NSC mitochondrial function and cell proliferation disorders.Pioglitazone,a well-known clinical drug,up-regulated NLRP6 expression to inhibit ECRG4 expression in its protection against corticosterone-induced NSC mitochondrial dysfunction and proliferation restriction.In conclusion,this study demonstrates that NLRP6 is essential to maintain mitochondrial homeostasis and proliferation in NSCs,and identifies NLRP6 as a promising therapeutic target for hippocampal neurogenesis decline linked to depression.