The Role And Mechanism Of IFN-γ Receptor In The Susceptibility To Chronic Social Defeat Stress In Mice

Objective: It has been reported that dysfunction of the immune system is an important pathological mechanism of social avoidance.For example,interference with the recruitment of T cells to meninges can induce social avoidance in C57BL/6J mice,however,T cells cannot penetrate the blood-brain barrier(BBB).This suggests that their regulation effects on the central nervous system may be through cytokines.Interferon-γ(IFN-γ)secreted by T cell can penetrates BBB and plays a central regulatory role through its receptor,interferon-γ receptor 1(IFNGR1).IFN-γ has been found to have an essential role in inhibitory current through IFNGR1 in medial prefrontal cortex(m PFC)and contribute to cognitive dysfunction.However,the role of IFNGR1 on social behavior under stress states has not been revealed.This study focused on the mechanism of IFN-γ receptor IFNGR1 in social deficit induced by chronic social defeat stress(CSDS).Methods: Social deficit induced by CSDS and Social interaction test(SIT)were utilized to detect the social avoidance behaviors;Western blot(WB)were conducted to measure the expression of IFNGR1 in m PFC of susceptible C57BL/6J mice;Intracerebroventricular microinjection of LV-IFNGR1 was used to measure the effect of IFNGR1 on social avoidance behaviors induced by CSDS;Subthrereshold social defeat stress(SSDS)after intracerebroventricular microinjection of LV-IFNGR1-shRNA was used to detect the effect of IFNGR1 knock-down on stress susceptibility.Miniature inhibitory postsynaptic current(m IPSCs)in m PFC neurons was recorded by patch clamp.Results:(1)Social avoidance behaviors were induced by CSDS in susceptible C57BL/6J mice.Compared with control group,sucrose preference and social interaction ratio of susceptible C57BL/6J mice were remarkably decreased.(2)The protein level of IFNGR1 in m PFC of susceptible C57BL/6J mice was remarkably decreased.(3)IFNGR1 was co-located with IBA1 and Neu N from m PFC brain region.IFNGR1 was mainly expressed in microglia according to the fluorescence intensity.It was also expressed in neurons,but with no expression in astrocytes.(4)The number of microglial cell in CSDS susceptible C57BL/6J mice was significantly increased.(5)The fluorescence intensity of CD68,a marker of M1 type microglia,in CSDS susceptible C57BL/6J mice was remarkably increased.(6)LV-IFNGR1 significantly promoted the expression of IFNGR1.(7)Overexpression of IFNGR1 in the m PFC remarkbly enhanced interaction ratio,reduced the immobility time in FST and TST.(8)LV-sh RNA remakly decreased the expression of IFNGR1.(9)Slience of IFNGR1 in m PFC promoted C57BL/6J mice to be more stess suscptible.(10)Slience of IFNGR1 in m PFC did not affect the anxiety behavior in C57BL/6J mice.(11)Genetic knock-down of IFNGR1 in m PFC significantly increased the number of microglial cell.(12)Genetic knock-down of IFNGR1 in m PFC significantly increased the fluorescence intensity of CD68.(13)Fluoxetine alleviated the depressive-like behavior induced by CSDS and restored the expression of IFNGR1 in the m PFC.(14)Specific knock-down of IFNGR1 in m PFC remarkably reduced the frequency and amplitude of m IPSCs.Conclusion: IFN-γ receptor IFNGR1 has been significantly down-regulated in the m PFC of CSDS susceptible C57BL/6J mice,CSDS activates the microglia in susceptible C57BL/6J mice.Overexpression of IFNGR1 in m PFC significantly alleviates the depression-like behavior in susceptible C57BL/6J mice.Genetic knock-down of IFNGR1 in the m PFC increases stress susceptibility and activates microglia in C57BL/6J mice.Genetic knock-down of IFNGR1 also reduces the amplitude and frequency of inhibitory current in the mPFC.