ROLES OF GPR18 AND MTORC1 IN SPONTANEOUS RECOVERY FROM LIPOPOLYSACCHARIDE-INDUCED DEPRESSION-LIKE STATE IN MICE

Abstract Background Stress resilience is an ability to resist and bounce back from stress. Whereas the mechanisms underlying the stress resistance have been studied extensively using animal models, such as a chronic social defeat stress model, those underlying spontaneous recovery from stress and depression are not well understood. We previously demonstrated that intracerebroventricular infusion of resolvin D2 (RvD2), a bioactive metabolite derived from docosahexaenoic acid, produces antidepressant-like effects via GPR18 and mechanistic target of rapamycin complex 1 (mTORC1) in an inflammation-induced depression model, namely lipopolysaccharide (LPS)-challenged mice (Deyama et al. 2017). We also reported that the medial prefrontal cortex (mPFC) and dorsal hippocampus (dHPC) are important brain regions for mediating the antidepressant-like effects of RvD2 (Deyama et al. 2017). However, the physiological and pathophysiological roles of endogenous RvD2– GPR18 signaling in the brain are largely unknown. Aim & Objectives Here, we examined the roles of GPR18 and mTORC1 in the mPFC and dHPC in spontaneous recovery from LPS-induced depression-like behaviors (Laumet et al. 2018). Methods LPS (0.8 mg/kg) was intraperitoneally injected into male C57BL/6J mice (7-10 weeks). To examine the role of GPR18 in spontaneous recovery from LPS-induced depression-like state, subcutaneous (10 mg/kg, s.c.), intra-mPFC, or intra-dHPC administrations (10 ng/side) of a GPR18 antagonist PSB-CB5 were conducted 24, 48, and 71 h after the LPS challenge. Likewise, to evaluate the role of mTORC1, intra-mPFC or intra- dHPC infusions of an mTORC1 inhibitor rapamycin (0.01 nmol/side) were performed 24, 48, and 71 h after the LPS challenge. LPS-induced depression-like state was evaluated by the forced swim test (FST) and female urine sniffing test (FUST). These tests were carried out 26 or 74 h after the LPS challenge. We also examined the effects of a single intra-mPFC or intra-dHPC infusion of RvD2 (0.3 ng/side) at 47 or 70 h after the LPS challenge on PSB-CB5- and rapamycin-induced impairment of spontaneous recovery from LPS-induced depression-like behaviors. Results Immobility in the FST and time spent sniffing female urine in the FUST were significantly increased and decreased, respectively, 26 h after the LPS challenge. These depression-like behaviors were not observed 74 h after LPS, indicating that spontaneous recovery from LPS-induced depression-like behaviors occurs within 3 days. However, mice repeatedly injected s.c. with PSB-CB5 still showed increased immobility in the FST 74 h after LPS, and this impairment of spontaneous recovery was canceled by intra-mPFC or intra-dHPC infusion of RvD2. The impairment of spontaneous recovery from LPS-induced depression-like behaviors was also observed in mice received repeated infusion of PSB-CB5 into the mPFC/dHPC. Moreover, repeated infusions of rapamycin into the mPFC, but not dHPC, impaired the spontaneous recovery, which was canceled by intra-mPFC RvD2 infusion. Discussion &Conclusion The present results demonstrate that activation of GPR18 in the mPFC and dHPC and of mTORC1 in the mPFC mediates the spontaneous recovery from LPS-induced depression-like behaviors. These findings suggest that the impairment of GPR18 and/or mTORC1 signaling could lead to deficits in stress resilience, which results in depression. References Deyama S, Ishikawa Y, Yoshikawa K, Shimoda K, Ide S, Satoh M, Minami M. (2017) Resolvin D1 and D2 reverse lipopolysaccharide-induced depression-like behaviors through the mTORC1 signaling pathway. Int J Neuropsychopharmacol, 20: 575-584. Laumet G, Edralin JD, Chiang AC, Dantzer R, Heijnen CJ, Kavelaars A. (2018) Resolution of inflammation- induced depression requires T lymphocytes and endogenous brain interleukin-10 signaling. Neuropsychopharmacology, 43: 2597-2605.