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Published on: May 15, 2019
The antidepressant roles of Wnt2 and Wnt3 in stress-induced depression-like behaviors
1Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, CAS Center for Excellence in Brain Science and Intelligence Technology, School of Medicine, Shandong University, Jinan, Shandong, China.
Abstract:
Wnts-related signaling pathways have been reported to play roles in the pathogenesis of stress-induced depression-like behaviors. However, there is relatively few direct evidence to indicate the effect of Wnt ligands on this process. Here, we investigated the role of Wnts in mediating chronic restraint stress (CRS)-induced depression-like behaviors. We found that CRS induced a significant decrease in the expression of Wnt2 and Wnt3 in the ventral hippocampus (VH) but not in the dorsal hippocampus. Knocking down Wnt2 or Wnt3 in the VH led to impaired Wnt/β-catenin signaling, neurogenesis deficits and depression-like behaviors. In contrast, overexpression of Wnt2 or Wnt3 reversed CRS-induced depression-like behaviors. Moreover, Wnt2 and Wnt3 activated cAMP response element-binding protein (CREB) and there was CREB-dependent positive feedback between Wnt2 and Wnt3. Finally, fluoxetine treatment increased Wnt2 and Wnt3 levels in the VH and knocking down Wnt2 or Wnt3 abolished the antidepressant effect of fluoxetine. Taken together, our study indicates essential roles for Wnt2 and Wnt3 in CRS-induced depression-like behaviors and antidepressant.
Insights
Wnt2 and Wnt3 are crucial in chronic stress and depression. Lowering these Wnt ligands in the ventral hippocampus causes depression-like behaviors, while increasing them reverses these effects, highlighting their antidepressant potential.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Wnt signaling pathways are implicated in stress-induced depression.
- Direct evidence for Wnt ligand involvement in depression pathogenesis is limited.
Purpose of the Study:
- To investigate the role of Wnt ligands in chronic restraint stress (CRS)-induced depression-like behaviors.
- To explore the therapeutic potential of Wnt2 and Wnt3 in depression.
Main Methods:
- Investigated Wnt2 and Wnt3 expression in the ventral hippocampus (VH) after CRS.
- Utilized knockdown and overexpression techniques for Wnt2 and Wnt3 in the VH.
- Assessed Wnt/β-catenin signaling, neurogenesis, and depression-like behaviors.
- Examined the interaction between Wnt ligands and CREB (cAMP response element-binding protein).
- Evaluated the effect of fluoxetine on Wnt levels and antidepressant efficacy.
Main Results:
- CRS decreased Wnt2 and Wnt3 expression in the VH.
- Wnt2/Wnt3 knockdown impaired Wnt/β-catenin signaling, reduced neurogenesis, and induced depression-like behaviors.
- Wnt2/Wnt3 overexpression reversed CRS-induced depression-like behaviors.
- Wnt2 and Wnt3 activated CREB, with evidence of CREB-dependent positive feedback.
- Fluoxetine increased VH Wnt2/Wnt3 levels, and Wnt2/Wnt3 knockdown blocked fluoxetine's antidepressant effect.
Conclusions:
- Wnt2 and Wnt3 play essential roles in mediating CRS-induced depression-like behaviors.
- Wnt2 and Wnt3 signaling in the VH is critical for antidepressant effects.
- Targeting Wnt2 and Wnt3 represents a potential therapeutic strategy for depression.
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