Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation (HUST), Wuhan, 430030, China; Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China; The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, China.
Pharmacol Res. 2021 Jan;163:105355. doi: 10.1016/j.phrs.2020.105355. Epub 2020 Dec 4.
Adaptive responses to stress are critical to enhance physical and mental well-being, but excessive or prolonged stress may cause inadaptability and increase the risks of psychiatric disorders, such as depression. GABAR signaling is fundamental to brain function and has been identified in neuropsychiatric disorders. KCTD12 is a critical auxiliary subunit in GABAR signaling, but its role in mental disorders, such as depression is unclear. In the present study, we used a well-validated mice model, chronic social defeat stress (CSDS) to investigate behavioral responses to stress and explore the role of Kctd12 in stress response, as well as the relevant mechanisms. We found that CSDS increased the expression of Kctd12 in the dentate gyrus (DG), a subregion of hippocampus. Overexpression of Kctd12 in DG induced higher responsiveness to acute stress and increased vulnerability to social stress in mice, whereas knock-down of Kctd12 in DG prevented the social avoidance. Furthermore, an increased expression of GABA receptor 2 (GB2) in the DG of CSDS-treated mice was observed, and CGP35348, an antagonist of GABAR, improved the stress-induced behavior responses along with suppressing the excess expression of Kctd12. In addition, Kctd12 regulated the excitability of granule cell in DG, and the stimulation of neuronal activity by silencing Kctd12 contributed to the antidepressant-like effect of fluoxetine. These findings identify that the Kctd12 in DG works as a critical mediator of stress responses, providing a promising therapeutic target in stress-related psychiatric disorders, including depression.
适应压力对于增强身心健康至关重要，但过度或长期的压力可能导致适应不良，并增加精神障碍（如抑郁症）的风险。GABAR 信号对于大脑功能至关重要，已在神经精神障碍中得到证实。KCTD12 是 GABAR 信号的关键辅助亚基，但它在精神障碍（如抑郁症）中的作用尚不清楚。在本研究中，我们使用了一种经过充分验证的小鼠模型，即慢性社交挫败应激（CSDS），以研究应激反应的行为表现，并探讨 Kctd12 在应激反应中的作用及其相关机制。我们发现 CSDS 增加了海马亚区齿状回（DG）中 Kctd12 的表达。DG 中 Kctd12 的过表达诱导急性应激反应增加，并使小鼠对社交应激的易感性增加，而 DG 中 Kctd12 的敲低则阻止了社交回避。此外，在 CSDS 处理的小鼠的 DG 中观察到 GABA 受体 2（GB2）的表达增加，GABAR 的拮抗剂 CGP35348 改善了应激诱导的行为反应，同时抑制了 Kctd12 的过度表达。此外，Kctd12 调节 DG 颗粒细胞的兴奋性，沉默 Kctd12 可刺激神经元活动，有助于氟西汀的抗抑郁样作用。这些发现表明 DG 中的 Kctd12 作为应激反应的关键介质发挥作用，为应激相关精神障碍（包括抑郁症）提供了有前途的治疗靶点。
