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Downregulation of hippocampal SIRT6 activates AKT/CRMP2 signaling and ameliorates chronic stress-induced depression-like behavior in mice


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· 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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We thank Prof. Yi Yang, Ningxia Medical University, for providing antibodies (anti-AKT and anti-phospho-AKT). In addition, we thank Prof. Li-jun Zhao, Shaanxi Normal University, for gifting HT-22 cells. This study was also supported by Fundamental Research Fund for the Central Universities (GK202003054) and Natural Science Basic Research Plan in Shaanxi Province of China (No. 2019JM-285).

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HQ and WL conceived and designed the study, and wrote the manuscript. WL and XL performed the experiments and analyzed the data. All authors read and approved the manuscript.

Corresponding author

Correspondence to Hui Qiao.

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The authors declare no competing interests.

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Li, W., Liu, X. & Qiao, H. Downregulation of hippocampal SIRT6 activates AKT/CRMP2 signaling and ameliorates chronic stress-induced depression-like behavior in mice. Acta Pharmacol Sin 41, 1557–1567 (2020).

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  • AKT
  • CRMP2
  • chronic unpredictable stress
  • depression-like behaviors
  • SIRT6

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