Journal
ACTA PHARMACOLOGICA SINICA
Volume 41, Issue 12, Pages 1557-1567Publisher
NATURE PUBL GROUP
DOI: 10.1038/s41401-020-0387-5
Keywords
AKT; CRMP2; chronic unpredictable stress; depression-like behaviors; SIRT6
Funding
- Fundamental Research Fund for the Central Universities [GK202003054]
- Natural Science Basic Research Plan in Shaanxi Province of China [2019JM-285]
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Sirtuin 6 (SIRT6) has been reported to play a key role in cognitive function and mood regulation, yet its role in mood disorders is not completely understood. Here, we confirmed that knockdown of hippocampal SIRT6 alleviated depression-like behaviors induced by chronic unpredictable stress (CUS) in mice. Our in vitro data showed that SIRT6 negatively regulated protein kinase B (AKT) signaling by deacetylating histone 3 at Lys9 and Lys56. Knockdown of SIRT6 significantly increased AKT phosphorylation activity, while decreased collapsin response mediator protein 2 (CRMP2) phosphorylation activity. Furthermore, pharmacologic inhibition of SIRT6 by ferulic acid (FA) (40 or 80 mg center dot kg(-1) per day, i.g.) could activate AKT/CRMP2 pathway in vitro, which has been proved to exert an antidepressant-like effect on CUS-induced depressive models. In conclusion, our study suggested that hippocampal SIRT6 contributes to the performance of depression-like behaviors by suppressing AKT/CRMP2 signaling, and FA ameliorates CUS-induced depression-like behaviors in mice as a potential pharmacologic inhibitor of SIRT6.
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