Deficits in KCC2 and activation of the HPA axis lead to depression-like behavior following social defeat

Background: Chronic social stress triggers the development of major depression in humans and depression-like behavior in animal models. Hyperexcitability of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of depression. The HPA axis is tightly controlled by GABAergic inhibition at the level of corticotrophin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus. Recently, our lab has demonstrated plasticity in GABAergic control of the HPA axis following stress, involving downregulation of the K+/Clco-transporter 2 (KCC2) which is critical for the inhibitory actions of GABA. The purpose of this study was to determine if chronic social defeat stress activates the HPA axis using similar mechanisms which may contribute to the development of depression-like behavior. Methods: The activation of the HPA axis following social defeat was quantified by measuring circulating levels of corticosterone (CORT). The role of KCC2 in activation of the HPA axis following social defeat was assessed by measuring KCC2 levels in the PVN by Western blot analysis. The impact of HPA axis activation on depression-like behavior was examined using the forced swim test. The therapeutic potential of blocking the activation of the HPA axis for depression-like behavior was determined by pharmacological blockade of the HPA axis activation, using Antalarmin. Results: Here, we demonstrate that chronic social defeat stress increased plasma levels of CORT and depression-like behavior in submissive mice. The activation of the HPA axis in submissive mice following chronic social defeat stress was associated with a dephosphorylation and downregulation of KCC2 in the PVN, which has previously been demonstrated to play a key role in mounting the physiological response to stress. Elevations in corticosterone levels and the development of depression-like behavior were restricted to submissive mice and were not observed in dominant animals. Treatment of dominant mice with exogenous corticosterone induced submissive behaviors and depression-like behaviors in these animals. In addition, blocking CRH signaling with Antalarmin prevented the social stress-induced development of depression-like behavior in submissive mice. Conclusions: Our study suggests that plasticity in the GABAergic regulation of the HPA axis may underlie elevations in corticosterone following chronic social defeat and that blocking the activation of the HPA axis may have therapeutic potential to combat social stress-induced depression.