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.
Highlights
Major depression is a widespread psychiatric disorder with very high prevalence rate up to 15% in the world.[1]
Lenti-siWnt[2] or Lenti-siWnt[3] injection significantly decreased the level of p-GSK3β (Ser9) and nuclear β-catenin compared with Lenti-siSCR injection (Figure 2g; p-GSK3β: F2,15 = 19.717, P o 0.001, one-way analysis of variance (ANOVA); post hoc test, Lenti-siWnt[2], P o 0.001; LentisiWnt[3], P = 0.001; Figure 2h; nuclear β-catenin: F2,15 = 39.312, Po 0.001, one-way ANOVA; post hoc test, Lenti-siWnt[2], Po 0.001; Lenti-siWnt[3], P o 0.001), which suggested that knockdown of Wnt[2] or Wnt[3] led to impaired Wnt/β-catenin signaling
The result showed that there was a significant decrease in BrdU+-labeled cells 2 h after BrdU injection in the Lenti-siWnt[2] or Lenti-siWnt[3] group compared with Lenti-siSCR group (Figure 2j; F2,15 = 26.248, Po 0.001, one-way ANOVA; post hoc test, Lenti-siWnt[2], P o 0.001; Lenti-siWnt[3], Po 0.001), which suggested that knockdown of Wnt[2] or Wnt[3] impaired cell proliferation in the adult ventral hippocampus (VH)
Summary
Major depression is a widespread psychiatric disorder with very high prevalence rate up to 15% in the world.[1]. GSK3 is primarily regulated by Wnt,[10] and interestingly, it has been shown that Wnt/β-catenin signaling participates in depression disorders.[11,12,13] The activation of Wnt/ β-catenin signaling promotes antidepressant effect, whereas the blockade of Wnt/β-catenin signaling increases depression behaviors.[3,14,15,16,17,18]. Chronic stress is a risk factor for developing psychiatric diseases, such as major depression and anxiety disorders.[19] Increasing evidence shows that some Wnt-related signaling molecules are altered under stress condition. We have used CRS in mice as a useful animal model of depression and aimed to investigate whether selective Wnts participated in stressinduced depression-like behaviors
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