The Effect And Mechanism Of Ketamine On Social Dysfunction Induced By Chronic Social Defeat Stress In Mice

Objective: It is known that various diseases are accompanied by the occurrence of social dysfunction.In animal experiments,mice can exhibit social dysfunction after chronic social defeat stress(CSDS).As an N-methyl-D-aspartic acid receptor(NMDAR)antagonist,ketamine has been shown to relieve depression-like behavior in CSDS mice rapidly.However,the role of ketamine on social dysfunction caused by stress is unclear.This study mainly explored the role and mechanism of ketamine on social dysfunction caused by CSDS.Methods: Mice were exposed to CSDS,social interaction test,three-chambered social test were used to evaluate the social function of mice.The tail suspension test was used to evaluate the depression-like behavior of mice,and the open field test was used to evaluate the motor function of mice.Western blot(WB)was used to detect the expression levels of glutamate receptor in dorsal cornu ammonis 1(d CA1)and dorsal cornu ammonis 3(d CA3).After intraperitoneal injection of ketamine or administration of ketamine into d CA1 and d CA3,the effects of ketamine on the social behavior of mice were observed.The glutamatergic neuron in d CA3 was regulated by optogenetics,and the effects of ketamine on the social function of CSDS mice were observed.Results:(1)Compared with control mice,the social interaction ratio of CSDS-treated mice(control: 202.9 ± 34.31%,susceptible: 50.12 ± 6.13%;n = 14-26,P < 0.001)and time spent in the target area(control: 67.21 ± 4.55 s,susceptible: 23.83 ± 3.72 s;n = 14-18,P < 0.001)were significantly decreased,indicating that CSDS induces social avoidance in mice.(2)Intraperitoneal administration of ketamine significantly reduced the immobility time of CSDS-treated mice in tail suspension test(control+sal: 181.4 ± 17.5 s,CSDS+sal: 271.2 ± 7.6 s,CSDS+5 mg/kg ket: 220.0 ± 15.4 s,CSDS+10 mg/kg ket: 161.6 ± 14.2 s,CSDS+20 mg/kg ket:7 148.1 ± 27.7 s;n = 5-11,P < 0.01).Low dosage(5 mg/kg)of ketamine increased the social interaction ratio of CSDS-treated mice significantly(control+sal:134.0 ± 7.8%,CSDS+sal: 39.93 ± 9.1%,CSDS+5 mg/kg ket: 131.3 ± 23.2%;n = 8-9,P < 0.01),reversed the social preference(control+sal: 0.06 ± 0.03,CSDS+sal:-0.32 ± 0.06,CSDS+5 mg/kg ket: 0.06 ± 0.07;n = 10-11,P <0.001).While increasing the dose of ketamine had no effects on the social interaction ratio and social preference.Ketamine had no effects on the motor function of mice(control+sal: 4976.0 ± 443.7 cm,control+5 mg/kg ket: 5480.0 ± 453.8 cm,CSDS+sal: 5138.0 ± 428.7 cm,CSDS+5 mg/kg ket: 5131.0 ± 260.3 cm,CSDS+10 mg/kg ket: 5496.0 ± 401.1 cm,CSDS+20 mg/kg ket: 4788.0 ± 394.9 cm;n = 10-11,P = 0.78).It was shown that only intraperitoneal injection of low dosage(5 mg/kg)of ketamine could significantly improve the social dysfunction of mice caused by CSDS,and had no effects on the motor function.(3)The surface expression of Glu A1 subunit(control: 1.00 ± 0.07,CSDS: 0.32 ± 0.06;n = 8-9,P < 0.001)and Glu A2 subunit(control: 1.00 ± 0.10,CSDS: 0.36 ± 0.13;n = 3-4,P < 0.01)in the d CA3 of CSDS-treated mice were decreased.The expression of Glu A1 subunit in the cytoplasm was also significantly reduced(control: 1.00 ± 0.09,CSDS: 0.61 ± 0.04;n = 8-11,P < 0.001)compare with control.The expression of phosphorylated cyclic adenosine monophosphate response element binding protein(p-CREB)was significantly reduced(control: 1.00 ± 0.07,CSDS: 0.45 ± 0.01,n = 4-8,P < 0.001)compare with control,indicating that CSDS decreases the expression of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor(AMPA)receptor in the membrane and p-CREB in the d CA3.(4)After administration of ketamine in the d CA1,the social interaction ratio(CSDS+sal: 66.87 ± 11.37%,CSDS+ket: 66.0 ± 13.4%;n = 10-13,P = 0.96)and social preference(CSDS+sal:-0.33±0.04,CSDS+ket:-0.40 ± 0.05;n = 12,P = 0.94)of CSDS-treated mice showed no significant change,indicating that d CA1 is not involved in the effect of ketamine.After administration of ketamine in the d CA3,the social interaction ratio(CSDS+sal: 57.47 ± 12.73%,CSDS+ket: 123.6 ± 6.6%;n = 10-14,P < 0.001)and social preference(CSDS+sal:-0.45 ± 0.07,CSDS+ket: 0.06 ± 0.05;n = 10-11,P < 0.001)of CSDS-treated mice significantly increased,suggesting that administration of ketamine in d CA3 could significantly improve the social dysfunction of CSDS-treated mice.(5)After administration of ketamine in the d CA1,the immobility time of CSDS-treated mice(CSDS+sal:246.80 ± 31.96 s,CSDS+ket: 190.77 ± 21.57 s;n = 9-13,P = 0.25)and distance travelled(CSDS+sal: 5036.03 ± 341.12 cm,CSDS+ket: 4683.34 ± 259.53 cm;n = 8-10,P = 0.46)remained unchanged.Administration of ketamine in the d CA3,the immobility time(CSDS+sal: 278.12 ± 13.00 s,CSDS+ket: 253.62 ± 14.74 s;n = 10-14,P = 0.84)and distance travelled(CSDS+sal: 4296.19 ± 468.56 cm,CSDS+ket: 4165.62 ± 350.03 cm;n = 8-10,P = 0.36)of CSDS-treated mice showed no significant change,indicating that administration of ketamine in the d CA1 and d CA3 of CSDS-treated mice has no obvious effects on the motor function and desperate behavior.(6)Inhibition of the glutamatergic neuron in d CA3 by optogenetics reduced the social interaction ratio(CSDS+EYFP: 140.14 ± 22.50%,CSDS+Np HR3.0: 73.89 ± 14.24%;n = 9,P < 0.05)and social preference(CSDS+EYFP: 0.164 ± 0.059,CSDS+Np HR3.0:-0.290 ± 0.055;n = 9,P < 0.001)of CSDS-treated mice,indicating that ketamine improves social dysfunction in CSDS-treated mice by inhibiting glutamatergic neuron in the d CA3.Conclusion: Intraperitoneal injection of 5 mg/kg ketamine can improve the social dysfunction in CSDS-treated mice,which is related to the inhibition of glutamatergic neuron in the hippocampal d CA3 by ketamine.