The effects of Kctd12, an auxiliary subunit of GABAB receptor in dentate gyrus on behavioral response to chronic social defeat stress in mice

Abstract

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_BR signaling is fundamental to brain function and has been identified in neuropsychiatric disorders. KCTD12 is a critical auxiliary subunit in GABA_BR 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_B receptor 2 (GB2) in the DG of CSDS-treated mice was observed, and CGP35348, an antagonist of GABA_BR, 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.

Keywords: CGP35348 (CID: 107699); Dentate gyrus; Depression; Fluoxetine; Fluoxetine (CID: 62857); GABA(B)R antagonists; Kctd12; Neuronal excitability.