The Effect Of Interferon-γ Receptor On Chronic Social Defeat Stress-induced Depressive-like Behavior In Mice

Objective: Interferon γ(IFN-γ)is a type II interferon involved in immune regulation,also known as immunomodulatory interferon,which mainly produced by activated T cells and natural killer cell(NK).It is also a type of so-called Lymphokine.Functional IFN-γ receptor(IFNGR)is composed of IFNGR1,IFNGR2 and related signaling pathway.IFNGR1 is responsible for ligand binding.Many clinical studies have pointed out that the treatment of chronic hepatitis C with type I interferon(interferon α)increases the susceptibility of patients to depression.And researches have suggest that IFNGR1 plays a role in social behavior by regulating neuronal connectivity.So we aim to reveal the role of IFNGR1 in chronic social defeat stress-induced depressive-like behavior in mice.Methods: Chronic social defeat stress(CSDS)was used to induce depressive-like behavior in mice.Sucrose preference test(SPT)and social interaction test(SIT)were used to evaluate the depressive-like behavior in mice;enzyme linked immunosorbent assay was used to detect the expression of IFN-γ in different brain regions and peripheral blood;q PCR and western blotting were used to detect the expression of IFNGR1 in various brain regions.Lentivirus-mediated overexpression was used to measure the behavioral changes in mice;mouse IFN-γ recombinant protein(recombinant mouse IFN-gamma protein)was given by intracerebroventricular microinjection to activate IFN-γ and detect the behavioral changes in mice.Results:(1)After ten consecutive days of CSDS,mice showed depressive-like behavior in behavioral test.Compared with control,the sucrose preference ratio of CSDS mice was decreased significantly(control: 82.23 ± 1.18%,CSDS: 51.78 ± 4.13%,P < 0.001),and social interaction ratio was also significantly reduced(control: 1.39 ± 0.09,CSDS: 0.51 ± 0.05,P < 0.001).(2)Compared with control group,the protein level of IFN-γ in the blood and various brain regions had no changes in CSDS mice.(3)The gene expression of IFNGR1 in the m PFC of CSDS mice was significantly decreased(control: 1.00 ± 0.04,CSDS: 0.79 ± 0.04,n=9-15,P < 0.01);Compared with the control(1.00 ± 0.02),the gene expression of IFNGR1 in d HIP was also significantly reduced to 0.65 ± 0.05(n = 10-13,P < 0.0001).(4)Compared with control(1.00 ± 0.07),the protein level of IFNGR1 in the m PFC of CSDS mice was significantly reduced to 0.81 ± 0.04(n = 5-7,P < 0.05).(5)Overexpression of IFNGR1 in the m PFC increased the social interaction ratio(LV-GFP + con: n = 11,LV-IFNGR1 + con: n = 9,LV-GFP + CSDS: n = 10,LV-IFNGR1 + CSDS: n = 12).(6)Injection with recombinant mouse IFN-gamma(IFNG)in m PFC induced the depressive-like behavior in mice.Sucrose preference ratio of mice injected with IFNG was reduced significantly compared with the mice injected with vehicle(vehicle: 76.23 ± 2.06%,n = 8;IFNG: 62.78 ± 4.44%,n = 7,P < 0.05).Tail suspension test showed significantly increased immobility time in mice injected with IFNG compared with the vehicle mice(vehicle: 85.78 ± 7.68 sec;IFNG: 131.9 ± 8.99 sec,n = 22 mice/group,P < 0.001).Conclusion: After ten days of CSDS,the protein level of IFN-γ in the blood and various brain regions have no changes.Meanwhile,the gene and protein expression of IFN-γ receptor IFNGR1 are reduced significantly in the m PFC of CSDS mice.Overexpression of IFNGR1 in the m PFC alleviates CSDS-induced depressive-like behavior.Injection of IFN-γ recombinant proteins in the m PFC of normal mice induces the depression-like behavior,suggesting that IFNGR1 plays an important role in CSDS-induced depressive-like behavior in mice.