Effect Of Up-regultion Of αCaMKⅡ Activity In The Dentate Gyrus On Contextual Fear Extinction In Post-traumatic Stress Disoder Rats

Post-Traumatic Stress Disorder(PTSD)is a mental disease that occurs after traumatic event such as wars,accidents,and natural disasters,causing hyperarousal,excessive anxiety,depression and cognitive impairment.The impaired fear extinction is one of the hallmark symptoms of PTSD.However,to date,there is no effective treatment,so it is important to explore the pathological mechanism of PTSD.Here,the PTSD rat model was established by single prolonged stress(SPS).Then,we examined the hippocampus-related cognitive function,long-term depression(LTD)of the medial perforant path(MPP)in the dentate gyrus(DG)and αCaMKII activity in SPS model rats.The main results are as follows:1)The behavioral data have shown that SPS model rats have impaired fear extinction;2)The invitro electrophysiological data have shown impaired LTD at MPP pathway of DG region in SPS model rats;3)Western blotting data have shown increased phosphorylation of CaMKII(Thr286)in DG region of SPS model rats.These results have indicated that the PTSD-like behavior may be related to the impaired LTD and increased αCaMKII activity in DG brain region of SPS model rats.In order to verify our hypothesis,we divided wild-type rats into strong fear-extinction group and weak-fear extinction group according to degree level of fear extinction,and then measured phosphorylation level of CaMKII(Thr286)of DG region in two groups.The main results are as follows:1)Western blotting results have shown increased phosphorylation of CaMKII(Thr286)in weak fear-extinction group compared to strong fear-extinction group;2)The weak fear-extinction group have shown significant higher level of anxietylike behavior than the strong fear-extinction group;To provide the mor supporting evidence for our hypothesis,which is that the impaired fear extinctionthe may be due to higher αCaMKII activity.We specifically upregulated αCaMKII in DG region by injecting pAAV—CMV-CaMKIIa-P2A-eGFP,and then examined the effect of specific upregulation of αCaMKII on contextual fear extinction and MPP-LTD of DG region.The main results are as follows:1)The specific up-regulation of αCaMKII in DG region impaired contextual fear extinction.2)The specific up-regulation of αCaMKII in DG region redued MPP-LTD.In summary,increase of αCaMKII activity impaired fear extinction and MPP-LTD of DG region.Our findings will provide new cue for the PTSD treatment.