Synapse and Neural Circuit Research Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892.
Genetic Engineering Core, National Eye Institute, NIH, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 2024 Jul 30;121(31):e2400078121. doi: 10.1073/pnas.2400078121. Epub 2024 Jul 26.
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.
目前治疗焦虑和抑郁障碍的方法存在明显的副作用和疗效有限等问题，这凸显了需要寻找其他分子靶点来改善药物治疗的必要性。在这里，我们发现了一个由慢性应激引发的分子级联反应，它会加剧焦虑和抑郁样行为。具体来说，慢性应激会增强Src 激酶的活性和钙调蛋白的酪氨酸磷酸化，从而减少肌球蛋白 Va（MyoVa）与神经连接蛋白 2（NL2）的相互作用，导致抑制性传递减少和焦虑样行为增加。重要的是，Src 的药理学抑制作用恢复了抑制性突触的缺陷，并有效地逆转了慢性应激小鼠的焦虑样行为，这一过程需要 MyoVa-NL2 相互作用。这些数据表明，焦虑和抑郁样表型在分子和行为水平上都具有可逆转性，并揭示了治疗焦虑和抑郁障碍的一个新靶点。
