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

Abstract

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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Acknowledgements

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.

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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). https://doi.org/10.1038/s41401-020-0387-5

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Keywords

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

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