Zhao Yan, Coulson Elizabeth J, Su Xingli, Zhang Junfeng, Sha Baoyong, Xu Hao, Deng Yating, Chen Yulong, Cao Jian, Wang Yunpeng, Wang Shuang
Institute of Basic Medicine Science & Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi 710021, China.
School of Biomedical Sciences, Faculty of Medicine and Queensland Brain Institute, the University of Queensland, Brisbane, QLD 4072, Australia.
iScience. 2021 Jan 8;24(2):102043. doi: 10.1016/j.isci.2021.102043. eCollection 2021 Feb 19.
Major depression is a prevalent and long-lasting psychiatric illness with severe functional impairment and high suicide rate. We have previously shown that the ventrolateral orbital cortex (VLO) plays a key role in the stress responses in mice, but the underlying mechanisms remains unclear. Here, we used proteomic method to identify differentially expressed proteins in VLO of chronic unpredictable mild stress (CUMS) mice. Of 4,953 quantified proteins, 45 proteins were differentially expressed following CUMS. The integrated pathway analyses identified 14-3-3ε and TrkB signaling as differentially downregulated in association with stress-induced depressive-like behaviors. 14-3-3ε overexpression in VLO relieved the depressive-like behaviors by rescue of Bad-mediated apoptosis. Moreover, treatment with the 14-3-3ε stabilizer FC-A precluded neuronal apoptotic signaling in VLO of depressed mice. Because 14-3-3ε provides significant protection against chronic stress, boosting 14-3-3ε expression, pharmacological stabilization of 14-3-3s (e.g. with FC-A) is identified as an exciting therapeutic target for major depression.
重度抑郁症是一种常见且持久的精神疾病，具有严重的功能障碍和高自杀率。我们之前已经表明，腹外侧眶额皮质（VLO）在小鼠应激反应中起关键作用，但其潜在机制仍不清楚。在这里，我们使用蛋白质组学方法来鉴定慢性不可预测轻度应激（CUMS）小鼠VLO中差异表达的蛋白质。在4953种定量蛋白质中，有45种蛋白质在CUMS后差异表达。综合通路分析确定14-3-3ε和TrkB信号通路与应激诱导的抑郁样行为相关的差异下调。VLO中14-3-3ε的过表达通过挽救Bad介导的凋亡减轻了抑郁样行为。此外，用14-3-3ε稳定剂FC-A治疗可阻止抑郁小鼠VLO中的神经元凋亡信号。由于14-3-3ε对慢性应激具有显著保护作用，因此提高14-3-3ε表达，14-3-3s的药理学稳定（例如用FC-A）被确定为重度抑郁症一个令人兴奋的治疗靶点。
