Department of Geriatrics, Tangdu hospital, Fourth Military Medical University, No. 1 Xinsi Road, Baqiao District, Xi'an, 710032, PR China.
Brain Res. 2012 Jul 27;1467:10-7. doi: 10.1016/j.brainres.2012.05.030. Epub 2012 May 22.
Aside from monoamine disturbances, recent evidence has implicated particular intracellular pathways, including Wnt signaling, in the pathogenesis of major depressive disorder. In the present study, we investigated the role of Wingless (Wnt)-Dishevelled (DVL)-glycogen synthase kinase 3β (GSK3β) signaling in the depression-like behaviors exhibited by rats exposed to chronic forced swim stress. We found that the rats subjected to forced swim stress for 14 consecutive days exhibited obvious depression-like behaviors and showed decreased levels of phosphorylated GSK3β and β-catenin in the hippocampus. Chronic citalopram treatment alleviated the depression-like behaviors and reversed the disruptions of the phosphorylated GSK3β and β-catenin in stressed rats. Furthermore, when the stressed rats with citalopram treatment received bilateral, dorsal hippocampus infusions of a DVL inhibitor, sulindac, the depression-like effects induced by chronic stress reappeared. These findings suggest that the Wnt-DVL-GSK3β signaling in the hippocampus is markedly involved in the pathophysiology of depression induced by chronic stress. The Wnt-DVL-GSK3β pathway may mediate the therapeutic action of citalopram, and the manipulation of DVL could be a target for novel antidepressants.
除了单胺类神经递质紊乱，最近的证据表明特定的细胞内信号通路，包括 Wnt 信号通路，与重度抑郁症的发病机制有关。在本研究中，我们调查了 Wingless（Wnt）-Dishevelled（DVL）-糖原合成酶激酶 3β（GSK3β）信号通路在慢性强迫游泳应激大鼠表现出的抑郁样行为中的作用。我们发现，连续 14 天接受强迫游泳应激的大鼠表现出明显的抑郁样行为，并且海马中磷酸化 GSK3β 和 β-连环蛋白的水平降低。慢性西酞普兰治疗减轻了抑郁样行为，并逆转了应激大鼠中磷酸化 GSK3β 和 β-连环蛋白的破坏。此外，当接受西酞普兰治疗的应激大鼠接受双侧海马背侧注射 DVL 抑制剂舒林酸时，慢性应激引起的抑郁样效应再次出现。这些发现表明，海马中的 Wnt-DVL-GSK3β 信号通路明显参与了慢性应激诱导的抑郁症的病理生理学。Wnt-DVL-GSK3β 通路可能介导西酞普兰的治疗作用，而 DVL 的操作可能是新型抗抑郁药的靶点。
