The Effect Of Ketamine Down-Regulation Neuroligin-1 In Hippocampus On Post-Traumatic Stress Disorder

Objective Intraoperative awareness is a common complication of general anesthesia,which can lead to severe neuropsychiatric disorders,such as post-traumatic stress disorder(PTSD).The main symptoms of PTSD include re-expericencing,avoiding and hyperarousal.PTSD make patients endure a tremendous burden.However the underlying pathophysiological mechanism of PTSD remains unclear,thus PTSD is a hotspot in the research.Neuroligin-1(NLGN-1)mainly expresses in excitatory synapses,which can mediate the expression of N-methyl-D-aspartate receptor(NMDAR)and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(AMPAR)by Postsynaptic density protein 95(PSD-95).NLGN-1 not only can regulate excitatory synaptic regeneration and excitatory signal transduction but also associates with cognition.In adition NLGN-1 plays a role in the pathophysiological mechanism of cognitive disease,like autism,alzheimer’s disease.NLGN-1 maybe play a role in the affective and learning dysfunction of PTSD,but the underlying mechanism remains unclear.Ketamine(KET)is a noncompetitive antagonist of NMDAR,which has the function of anti-anxiety and anti-depression.KET could be a new drug for PTSD treatment.This study applys the behavioral tests,molecular biology to explore the new pathophysiological mechanism of PTSD.The aimed as provide a new perspective for the prevention and treatment of PTSD.Method Sprague-Dawley(SD)male rats weighting 250-275g were constructed an animal model of PTSD by foot shock.The first set of SD rats was randomized into two groups:Control group,PTSD group.The fearing memory,and the ability of learning and memorizing were separately evaluated by the fear conditioning(FC)and Morris water maze(MWM)tests on 7 and 14 d after the model finished;at the same time,western blotting(WB)to measure the expression of NLGN-1 in prefrontal cortex,hippocampus and amydala.The second set of SD rats was randomized into one of the following four groups:Control + normal saline(NS),Control + KET,PTSD + NS,PTSD + KET.KET groups were treated with ketamine(2.5 mg/kg)by intraperitoneal injection beginning 30 min after the model finished and once a day forl4 days;NS groups only received a same amount of saline.The fearing memory,and the ability of learning and memorizing were separately evaluated by the fear conditioning(FC)and Morris water maze(MWM)tests on 14 d after model finished;at the same time,western blotting to measure the expression of NLGN-1,Neurexin-1(NRXN-1),PSD-95,NMDAR-2B,AMPA-GluRl in hippocampus.Results Firstly,whether in the 7 or 14 d,the percent of freezing time in total time in FC test was increased in PTSD group compared with Control group(P<0.05);in MWM training,PTSD group has longer escape latency than Control group at day 2,3,4(P<0.05);in MWM test,the percent of time in target quadrant between PTSD group and Control group has no significant(P>0.05).The protein levels of NLGN-1 in prefrontal cortex,hippocampus and amydala was no siginificant in seventh day(P>0.05);The protein levels of NLGN-1 in in prefrontal cortex and amydala were no siginificant,but signigicantly increased in hippocampus in PTSD group compared with Control group(P<0.05).Secondly,in FC test,compared with PTSD + NS group,the percent of freezing time in total time was decreased in PTSD + KET group(P<0.05);In MWM,compared with Control+NS group,the escape latency of PTSD+NS group was significantly increased at the day 2,3,4,5 of training(P<0.05).Compared with PTSD+NS group,the escape latency of PTSD+KET group was significantly decreased at the day 2,4,5 of training(P<0.05).There was no significant difference in the time spent in the target quadrant.Compared with PTSD + NS group,the protein levels of NLGN-1,NRXN-1,PSD-95,NMDAR-2B,AMPA-GluRl were decreased in PTSD + KET(P<0.05).Conclusion The PTSD group displayed increased fearing memory and hippocampal dependent spatial learning impairment.And at the same time,the expression of NLGN-1 in hippocampus was increased.KET could siginificantly attenuate fearing memory;improve the ability of hippocampus-dependent spatial learning and down-regulation the signaling pathway of NLGN-1 in PTSD,This study sugget that ket could treat PTSD by down-regulation the NRXN-1-NLGN-1-PSD-95 signaling pathway to inhibition of hyperexcitability in hippocampus.