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A Mouse Model of Subchronic and Mild Social Defeat Stress for Understanding Stress-induced Behavioral and Physiological Deficits
Published on: November 24, 2015
CDK5-mediated phosphorylation of Sirt2 contributes to depressive-like behavior induced by social defeat stress
Zheng Zhang1, Pei Zhang2, Guang-Jian Qi2
1Department of Neurobiology, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, Hubei Province 430030, PR China; Nanyang Medical College, Nanyang, Henan Province 473061, PR China; Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, Hubei Province 430030, PR China.
Abstract:
Major depressive disorder (MDD) is a common, severe and recurrent psychiatric disorder worldwide; however, the underlying neuropathological mechanisms remain elusive. Histone deacetylases (HDACs) appear to play an essential role in depression. As the class III HDACs, Sirt1 and Sirt2 have attracted the most interest in the nervous system. Indeed, chronic stress decreased Sirt1 activity and down-regulated Sirt1 gene expression in MDD. Nevertheless, there is a paucity of literature on the role of Sirt2. To study the role of Sirt2 we established a MDD mouse model in wild type and Sirt2 knockout C57BL/6 mice using social defeat stress (SDS). We found that a lack of Sirt2 blocked the development of SDS-induced depressive-like behavior. Moreover, SDS led to Sirt2 phosphorylation in the amygdala without changing total Sirt2 levels, and blocking the phosphorylation of Sirt2 by CDK5 at serine residues 368 and 372 prevented SDS-induced depressive-like behavior and Sirt2 nuclear import. We also discovered that SDS-induced Sirt2 phosphorylation was involved in VTA-amygdala modulation using TetTag-pharmacogenetic method. These results suggest that CDK5 mediates phosphorylation of Sirt2 in the amygdala and contributes to the depressive-like behavior induced by SDS. This study highlights that inhibiting CDK5-dependent phosphorylation of Sirt2 at serine residues 368 and 372 by myristoylated membrane-permeabilising peptide (Sirt2-p), rather than using non-specific sirtuin inhibitors, may be a novel strategy for treating depression.
Insights
Sirtuin 2 (Sirt2) phosphorylation in the amygdala contributes to depression. Inhibiting this specific Sirt2 modification, rather than general sirtuin activity, may offer a novel therapeutic strategy for major depressive disorder.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Major depressive disorder (MDD) is a prevalent psychiatric condition with unclear neuropathological origins.
- Histone deacetylases (HDACs), particularly Sirtuin 1 (Sirt1) and Sirtuin 2 (Sirt2), are implicated in depression.
- While Sirt1's role is documented, Sirt2's involvement in MDD remains under-investigated.
Purpose of the Study:
- To investigate the role of Sirtuin 2 (Sirt2) in the development of social defeat stress (SDS)-induced depressive-like behaviors.
- To elucidate the specific mechanisms underlying Sirt2's function in the context of MDD.
Main Methods:
- Establishment of an MDD mouse model using social defeat stress (SDS) in wild-type and Sirt2 knockout mice.
- Analysis of Sirt2 phosphorylation, total Sirt2 levels, and nuclear import in the amygdala.
- Pharmacogenetic manipulation using TetTag to investigate VTA-amygdala circuitry.
- Inhibition of CDK5-mediated Sirt2 phosphorylation using a specific peptide (Sirt2-p).
Main Results:
- Sirt2 knockout mice exhibited resistance to SDS-induced depressive-like behaviors.
- Social defeat stress (SDS) increased Sirt2 phosphorylation at serine residues 368 and 372 in the amygdala without altering total Sirt2 levels.
- Blocking CDK5-dependent Sirt2 phosphorylation prevented depressive-like behaviors and Sirt2 nuclear import.
- SDS-induced Sirt2 phosphorylation was found to modulate VTA-amygdala pathways.
Conclusions:
- CDK5-mediated phosphorylation of Sirt2 in the amygdala is a critical mechanism contributing to SDS-induced depressive-like behavior.
- Targeting CDK5-dependent Sirt2 phosphorylation at specific serine residues offers a potential novel therapeutic approach for MDD.
- This targeted inhibition may be more effective than non-specific sirtuin inhibitors for treating depression.
