The Role Of Hippocampal JAK2/STAT3 Pathway In The Antidepressant Effects Of Ketamine

Objective:Depression,affecting about 17%of the population and being the first cause of suicide,is one of the most prevalent psychiatric disorder.Ketamine,a commonly used general anesthetics,has been demonstrated to exert rapid and effective antidepressant effects and reduce thoughts of suicide in patients with treatment-resistant depression via regulating glutamate concentration in synaptic cleft,suppressing the inflammation,improving synaptic plasticity.The present studies show that the hippocampal synaptic plasticity,and the expression and phosphorylation of janus kinase 2(JAK2)and signal transducer and activator of transcription 3(STAT3),all deceased in depressed rats,while the JAK2/STAT3 signal pathway is regulated by brain-derived neurotrophic factor(BDNF).Therefore,we hypothesized that BDNF and its downstream JAK2/STAT3 signal pathway contributes to the antidepressant-like effects of ketamine.This research will explore the alterations and roles of JAK2/STAT3 signal pathway in the rapid antidepressant effects of ketamine and discuss the related mechanisms.Methods:The chronic unpredictable mild stress(CUMS)was used to set up a rat model of depression.One hundred male Sprague Dawley(SD)rats,weighting 220-250g,were divided into the following five groups(n=20)randomly and equally:Control(Con),CUMS+normal saline(CUMS+NS),CUMS+Ketamine(CUMS+Ket),CUMS+Vehicle+Ketamine(CUMS+Veh+Ket),CUMS+AG490+Ketamine(CUMS+AG490+Ket).Con were left undisturbed in home cages,the other four groups were exposed to chronic unpredictable mild stress for 42 days.Con,CUMS+NS and CUMS+Ket were intraperitoneal injected with normal saline or ketamine 10 mg/kg,and exposed to the open field test(OFT),elevated plus-maze test(EPM),sucrose preference test(SPT)and forced swimming test(FST)one hour later to test the depressive behaviors.After 35 days of CUMS,CUMS+Veh+Ket and CUMS+AG490+Ket were implanted with a single cannula into lateral ventricle,and intracerebroventricularly(i.c.v.)infused with DMSO and 50 nmol AG490 on day 38-42 respectively(both volume is 5ul),then intraperitoneal injected with ketamine 10 mg/kg and exposed to behavioral tests one hour later.Then,brain or hippocampus were collected.The expression of BDNF,t-JAK2,p-JAK2,t-STAT3,p-STAT3 and postsynaptic density 95(PSD95)in hippocampus were detected by Western Blot.The expression of JAK2 in hippocampus dentate gyrus were detected by immunofluorescence.Results:In the OFT,total distance among groups shows no significant difference(P>0.05).In the EPM,total crossings among groups shows no significant differences(P>0.05).In the FST,the immobility time was increased in CUMS+NS when compared with Con(P<0.001),was decreased in CUMS+Ket when compared with CUMS+NS(P<0.001),was increased in CUMS+AG490+Ket when compared with CUMS+Veh+Ket(P<0.001);the struggling time was increased in CUMS+NS when compared with Con(P<0.01),increased in CUMS+Ket when compared with CUMS+NS(P<0.05),was increased in CUMS+AG490+Ket when compared with CUMS+Veh+Ket(P<0.01).In the SPT,the sucrose consumption was decreased in CUMS+NS when compared with Con(P<0.001),increased in CUMS+Ket when compared with CUMS+NS(P<0.001),and decreased in CUMS+AG490+Ket when compared with CUMS+Veh+Ket(P<0.01).In Western Blot,the expression of BDNF,p-JAK2,t-JAK2,p-STAT3,t-STAT3 and PSD95 of hippocampus were decreased in CUMS+NS when compared with Con,increased in CUMS+Ket when compared with CUMS+NS.The expression of p-JAK2、t-JAK2、p-STAT3、t-STAT3 and PSD95 were decreased in CUMS+AG490+Ket when compared with CUMS+Veh+Ket(P<0.05),but the expression of BDNF shows no significant difference between the two groups(P>0.05).In immunofluorescence,the number of JAK2 in hippocampus dentate gyrus was decreased in CUMS+NS when compared with Con(P<0.05),increased in CUMS+Ket when compared with CUMS+NS(P<0.05),and decreased in CUMS+AG490+Ket when compared with CUMS+Veh+Ket(P<0.05).Conclusion:Ketamine has the ability to relieve animals’ depressive behavior,which is related to the enhancement of hippocampal synaptic plasticity mediated by JAK2/STAT3 signaling pathway.