α-MSH-catabolic enzyme prolylcarboxypeptidase in nucleus accumbens shell ameliorates stress susceptibility in mice through regulating synaptic plasticity  

作　　者：Qiao Deng Shao-qi Zhang Ping-fen Yang Wan-ting Dong Fang Wang Li-hong Long Jian-guo Chen 

机构地区：[1]Department of Pharmacology,School of Basic Medicine,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China [2]The Research Center for Depression,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China [3]The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province,Wuhan,430030,China [4]The Key Laboratory of Neurological Diseases(HUST),Ministry of Education of China,Wuhan,430030,China [5]Laboratory of Neuropsychiatric Diseases,The Institute of Brain Research,Huazhong University of Science and Technology,Wuhan,430030,China

出　　处：《Acta Pharmacologica Sinica》2023年第8期1576-1588,共13页中国药理学报（英文版）

基　　金：supported by National Natural Science Foundation of China (Grant No.82130110 [to JGC],U21A20363 [to FW],81872849 to [LHL]and 81721005 [to JGC]);the Foundation for National Key R&D Program of China (Grant No.SIT2030-Major project-2021ZD0202900 [to JGC]).

摘　　要：Emerging evidence demonstrates the vital role of synaptic transmission and structural remodeling in major depressive disorder.Activation of melanocortin receptors facilitates stress-induced emotional behavior.Prolylcarboxypeptidase(PRCP)is a serine protease,which splits the C-terminal amino acid ofα-MSH and inactivates it.In this study,we asked whether PRCP,the endogenous enzyme of melanocortin system,might play a role in stress susceptibility via regulating synaptic adaptations.Mice were subjected to chronic social defeat stress(CSDS)or subthreshold social defeat stress(SSDS).Depressive-like behavior was assessed in SIT,SPT,TST and FST.Based on to behavioral assessments,mice were divided into the susceptible(SUS)and resilient(RES)groups.After social defeat stress,drug infusion or viral expression and behavioral tests,morphological and electrophysiological analysis were conducted in PFX-fixed and fresh brain slices containing the nucleus accumbens shell(NAcsh).We showed that PRCP was downregulated in NAcsh of susceptible mice.Administration of fluoxetine(20 mg·kg^(−1)·d^(−1),i.p.,for 2 weeks)ameliorated the depressive-like behavior,and restored the expression levels of PRCP in NAcsh of susceptible mice.Pharmacological or genetic inhibition of PRCP in NAcsh by microinjection of N-benzyloxycarbonyl-L-prolyl-L-prolinal(ZPP)or LV-shPRCP enhanced the excitatory synaptic transmission in NAcsh,facilitating stress susceptibility via central melanocortin receptors.On the contrary,overexpression of PRCP in NAcsh by microinjection of AAV-PRCP alleviated the depressive-like behavior and reversed the enhanced excitatory synaptic transmission,abnormal dendritogenesis and spinogenesis in NAcsh induced by chronic stress.Furthermore,chronic stress increased the level of CaMKIIα,a kinase closely related to synaptic plasticity,in NAcsh.The elevated level of CaMKIIαwas reversed by overexpression of PRCP in NAcsh.Pharmacological inhibition of CaMKIIαin NAcsh alleviated stress susceptibility induced by PRCP knockdown.This st

关 键 词：stress susceptibility nucleus accumbens shell PROLYLCARBOXYPEPTIDASE synaptic transmission dendritogenesis spinogenesis 

分 类 号：R285.5[医药卫生—中药学]