The effects of Kctd12, an auxiliary subunit of GABAB receptor in dentate gyrus on behavioral response to chronic social defeat stress in mice
The effects of Kctd12, an auxiliary subunit of GABAB receptor in dentate gyrus on behavioral response to chronic social defeat stress in mice
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Kctd12（齿状回 GABA（B）受体的辅助亚基）对小鼠慢性社交失败应激行为反应的影响。
DOI：
10.1016/j.phrs.2020.105355
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发表时间：
2021-01-17
影响因子：
9.3
通讯作者：
Chen, Jian-Guo
中科院分区：
文献类型：
--
作者：
Deng, Si-Long;Hu, Zhuang-Li;Chen, Jian-Guo
对压力的适应性反应对增强身心健康至关重要，但过度或长期的压力可能会导致不适应，并增加患抑郁症等精神疾病的风险。GABA（B）R信号传导是脑功能的基础，并且已经在神经精神疾病中被确定。KCTD 12是GABA（B）R信号传导中的关键辅助亚基，但其在精神障碍如抑郁症中的作用尚不清楚。在本研究中，我们使用了一个良好的验证模型，慢性社会失败应激（CSDS）的小鼠研究应激的行为反应，并探讨Kctd 12在应激反应中的作用，以及相关机制。我们发现CSDS增加了海马齿状回（DG）中Kctd12的表达。DG中Kctd12的过表达诱导小鼠对急性应激的反应性增强，对社会应激的易感性增加，而DG中Kctd12的敲低阻止了社交回避。此外，观察到CSDS处理的小鼠DG中GABA（B）受体2（GB 2）的表达增加，并且GABA（B）R的拮抗剂CGP 35348沿着抑制Kctd 12的过度表达，改善应激诱导的行为反应。此外，Kctd12对DG颗粒细胞的兴奋性有调节作用，抑制Kctd12对DG颗粒细胞兴奋性的影响可能与氟西汀的抗抑郁作用有关。这些研究结果表明，DG中的Kctd12作为应激反应的重要介导者，为应激相关精神疾病（包括抑郁症）提供了一个有前途的治疗靶点。
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. GABA(B)R signaling is fundamental to brain function and has been identified in neuropsychiatric disorders. KCTD12 is a critical auxiliary subunit in GABA(B)R 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 gyms (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(B) receptor 2 (GB2) in the DG of CSDS-treated mice was observed, and CGP35348, an antagonist of GABA(B)R, 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 Kctdl 2 contributed to the antidepressant-like effect of fluoxe-tine. 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.