| BackgroundSchizophrenia is a chronic,disabling,and recurring lifelong disease that affects 1%of the world’s population,causing a serious social burden and becoming a global public health problem.The cause of schizophrenia may be genetic and/or environmental,but the specific mechanism is unknown.Dopamine and serotonin hypotheses remain the main hypotheses of this disease.The current drugs for the treatment of schizophrenia are dopamine receptor blockers and/or serotonin(5-HT)blockers.In recent years,some scholars have put forward hypotheses such as glutamate hypothesis andγ-aminobutyric acid for the analysis of the etiology of schizophrenia,but there are no relevant clinical treatment drugs.Sevoflurane is a volatile anesthetic widely used in clinical,and it is a potentiator ofγ-aminobutyric acid type A(GABA_A)receptors and can induce a rapidly,well-controlled and ultrashort action with low toxic and side effects.Studies have shown that low concentration sevoflurane has certain neuroprotective effects and it can improve cognitive function.Therefore,this study uses the mouse model of schizophrenia induced by MK801 to explore the role of low-concentration sevoflurane on schizophrenia mice and the mechanism therein,providing new ideas and strategies for the drug treatment of schizophrenia.PurposeTo explore the role of low concentration sevoflurane on MK801-induced schizophrenia mice and the possible molecular mechanism.Methods and results1.Establishment of MK801-induced mouse model of schizophrenia1.Establishment of MK801-induced mouse model of schizophreniaBalb/c pups at 7 days after birth(P7)were randomly divided into 2 groups.MK801 group mice were intraperitoneally injected with 0.5 mg/kg MK801 twice a day for 5consecutive days(P7-P11),and the control group mice were injected with an equal volume of Saline.Spontaneous activities in the open field and three-chamber tests were detected on P27-P30.2.Effect of sevoflurane on MK801-induced mouse model of schizophreniaAt P31,the mice in the MK801 group were randomly divided into 2 groups,the MK801 and the MK801+Sev group,and the mice in the MK801+Sev group were placed in the plexglas chamber and 1%sevoflurane was delivered via inlet of the chamber via a sevoflurane vaporizer at 1 L/min 30%oxygen balanced with nitrogen for 1 hour for consecutive 5 days.Ctrl group and MK801 group received identical gases without sevoflurane in the identical setting for 1 hour for consecutive 5 days.3.Laboratory testingBehavioral tests,immunohistochemistry,electrophysiology,and Western Blot tests were performed 1 week after the end of sevoflurane intervention.Result1.Behavioral results:1.1 Open field test:The total distance of the mice in the MK801 group were significantly decreased compared with that in the control group(Day1,p<0.001;Day2,p<0.001;Day3,p<0.001).After sevoflurane treatment,MK801+Sev group significantly increased the total distance compared with that in the MK801 group(Day1,p<0.001;Day2,p<0.01;Day3,p<0.01).Similarly,MK801 group crossed less squares than the control group(Day1,p<0.001;Day2,p<0.001;Day3,p<0.001)while the MK801+Sev mice had significantly high frequency of crossing squares compared with the MK801 group(Day1,p<0.01;Day2,p<0.05;Day3,p<0.001).1.2 Three-chamber test:Compared with the control group,the MK801 group mice spent less time sniffing the novel animal(p<0.01).After sevoflurane treatment,the MK801+Sev group mice spent more time sniffing the novel animal than the MK801 group mice(p<0.05).There was no significant difference between MK801+Sev group and the control group.2.Immunohistochemical results:the density of GAD67-positive cells and PV-positive cells in the laminar Ⅱ/Ⅲ of prefrontal cortex were significantly decreased in the MK801 group compared to that of control group(GAD67,p<0.001;PV,p<0.01).Compared with the MK801 group,the density of GAD67 and PV cells were significantly increased in the MK801+Sev group(GAD67,p<0.01;PV,p<0.05).There was no significant difference in the density of GAD67-positive cells and PV-positive cells in the laminar Ⅱ/Ⅲ of prefrontal cortex between the MK801+Sev group and the control group(p>0.05).3.Western Blot results:3.1 Compared with the control group,the expression of NR2A,NR2B,PSD95 in the prefrontal cortex of the MK801 group was significantly decreased(NR2A,p<0.01;NR2B,p<0.001;PSD95,p<0.001).Compared with the MK801 group,the expression of NR2A,NR2B and PSD95 in MK801+Sev group increased significantly(NR2A,p<0.05;NR2B,p<0.05;PSD95,p<0.05).There was no significant difference in the expression of the expression of NR2A,NR2B and PSD95 between MK801+Sev group and the control group(p>0.05).There were no significant differences in the expression of NR1 in the three groups(p>0.05).3.2 There was no significant differences in the expression of GABA_Aα1,GABA_Aβ2 and Gephyrin in the three groups(p>0.05).3.3 Compared with the control group,the expression of NRG1 and ErbB4 in the prefrontal cortex of the MK801 group was significantly reduced(NRG1,p<0,05;ErbB4,p<0.01).The expression of NRG1and ErbB4 in the MK801+Sev group was significantly increased,as compared to that of MK801 group(NRG1,p<0,05;ErbB4,p<0.01).There was no significant difference in the expression of NRG1 and ErbB4between the MK801+Sev group and the control group.4 Electrophysiological results:the amplitude of miniature excitatory postsynaptic current(mEPSC)and miniature inhibitory postsynaptic current(mIPSC)of pyramidal neurons in laminar Ⅱ/Ⅲ of prefrontal cortex were significantly decreased in the MK801 group compared to that of control group(mEPSC,p<0.001;mIPSC,p<0.001).The amplitude of mEPSC and mIPSC in the MK801+Sev group were significantly increased,as compared to that of MK801 group(mEPSC,p<0.001;mIPSC,p<0.01).There was no significant difference in amplitude of mEPSC and mIPSC between the MK801+Sev group and the control group(p>0.05).Compared with the control group,the frequency of mEPSC in the MK801 group was significantly increased(p<0.001).Compared with the MK801 group,the frequency of mEPSC in the MK801+Sev group was significantly decreased(p<0.05).There was no significant difference in the frequency of mEPSC between the MK801+Sev group and the control group(p>0.05).There was no significant difference in the frequency of mIPSC among the three groups(p>0.05).The E/I ratio in the MK801 group was higher than that of control group(p<0.001).Compared with the MK801 group,the E/I Ratio in the MK801+Sev group decreased significantly(p<0.01).There was no significant difference in the E/I Ratio between the MK801+Sev group and the control group(p>0.05).ConclusionLow concentration of sevoflurane can significantly reverse the neurobehavioral and neuropathological abnormalities of MK801-induced schizophrenia model mice and play a role in the treatment of schizophrenia,and the therapeutic effect may be related to the activation of NRG1/ErbB4 signaling pathway. 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