Neuron stem cell NLRP6 sustains hippocampal neurogenesis to resist stress-induced depression.
10.1016/j.apsb.2023.03.010
- Author:
Chuanfeng TANG
1
;
Qiaona WANG
1
;
Jingyan SHEN
1
;
Congying WANG
1
;
Hong DING
1
;
Shiyu WEN
1
;
Fan YANG
1
;
Ruiqing JIAO
1
;
Xingxin WU
1
;
Jianmei LI
1
;
Lingdong KONG
1
Author Information
1. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
- Publication Type:Journal Article
- Keywords:
Depressive-like behaviors;
ECRG4;
Mitochondrial function;
NLRP6;
Neural stem cells;
Pioglitazone;
Proliferation;
Stress resilience
- From:
Acta Pharmaceutica Sinica B
2023;13(5):2017-2038
- CountryChina
- Language:English
-
Abstract:
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 NSC-conditional 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.
