PDF(Pubmed)
Abstract：
Current treatments of anxiety and depressive disorders are plagued by considerable side effects and limited efficacies, underscoring the need for additional molecular targets that can be leveraged to improve medications. Here, we have identified a molecular cascade triggered by chronic stress that exacerbates anxiety- and depressive-like behaviors. Specifically, chronic stress enhances Src kinase activity and tyrosine phosphorylation of calmodulin, which diminishes MyosinVa (MyoVa) interaction with Neuroligin2 (NL2), resulting in decreased inhibitory transmission and heightened anxiety-like behaviors. Importantly, pharmacological inhibition of Src reinstates inhibitory synaptic deficits and effectively reverses heightened anxiety-like behaviors in chronically stressed mice, a process requiring the MyoVa-NL2 interaction. These data demonstrate the reversibility of anxiety- and depressive-like phenotypes at both molecular and behavioral levels and uncover a therapeutic target for anxiety and depressive disorders.
摘要：
目前焦虑和抑郁障碍的治疗受到相当大的副作用和有限的疗效的困扰。强调需要额外的分子靶标，可以利用改善药物。这里,我们已经确定了一个由慢性应激引发的分子级联反应,它加剧了焦虑和抑郁样行为.具体来说,慢性应激增强Src激酶活性和钙调蛋白的酪氨酸磷酸化，这减少了MyosinVa（MyoVa）与Neuroligin2（NL2）的相互作用，导致抑制传播减少和焦虑样行为增强。重要的是,Src的药理抑制作用可恢复抑制性突触缺陷，并有效逆转慢性应激小鼠的焦虑样行为，需要MyoVa-NL2交互的进程。这些数据证明了焦虑和抑郁样表型在分子和行为水平上的可逆性，并揭示了焦虑和抑郁障碍的治疗目标。
