The small GTPase Rac1 contributes to extinction of aversive memories of drug withdrawal by facilitating GABA A receptor endocytosis in the vmPFC

CORC > 昆明动物研究所 > 昆明动物研究所 > 动物模型与人类重大疾病机理重点实验室

	The small GTPase Rac1 contributes to extinction of aversive memories of drug withdrawal by facilitating GABA A receptor endocytosis in the vmPFC
	Li M 5; Zhang L 1; Ju YY 4,6; Wang WS 4,6; jgliu@mail.simm.ac.cn lxu@vip.163.com ; Kang S 6; Chen ZG 6; Wang YJ 6; Ding YQ 1; Ji H[3]7
刊名	Journal of neuroscience
	2017
卷号	期号:页码:Epub ahead of print
英文摘要	Extinction of aversive memories has been a major concern in neuropsychiatric disorders such as anxiety disorders and drug addiction. However, the mechanisms underlying extinction of aversive memories are not fully understood. Here, we report that extinction of conditioned place aversion (CPA) to naloxone-precipitated opiate withdrawal in male rats activates Rho GTPase Rac1 in the ventromedial prefrontal cortex (vmPFC) in a BDNF-dependent manner, which determines GABAA receptor (GABAAR) endocytosis via triggering synaptic translocation of activity-regulated cytoskeleton-associated protein (Arc) through facilitating actin polymerization. Active Rac1 is essential and sufficient for GABAAR endocytosis and CPA extinction. Knockdown of Rac1 expression within the vmPFC of rats using Rac1-shRNA suppressed GABAAR endocytosis and CPA extinction; whereas expression of a constitutively active form of Rac1 accelerated GABAAR endocytosis and CPA extinction. The crucial role of GABAAR endocytosis in the LTP induction and CPA extinction is evinced by the findings that blockade of GABAAR endocytosis by a dynamin function-blocking peptide (Myr-P4) abolishes LTP induction and CPA extinction. Thus, the present study provides first evidence that Rac1-dependent GABAAR endocytosis plays an crucial role in extinction of aversive memories and reveals the sequence of molecular events that contribute to learning experience modulation of synaptic GABAAR endocytosis.SIGNIFICANCE STATEMENTThis study reveals that Rac1-dependent GABAAR endocytosis plays an crucial role in extinction of aversive memories associated with drug withdrawal and identifies Arc as a downstream effector of Rac1 regulations of synaptic plasticity as well as learning and memory, thereby thereby suggesting therapeutic targets to promote extinction of the unwanted memories.
语种	英语
资助机构	This research was supported by grants 2013CB835100, 2015CB553502 (to J.-G. L.), 2013CB8351003(to L. X) from the Ministry of Science and Technology of China and by grants 81130087, 91232716 (to J.-G. L.) from the Foundation of National Natural Science of China and by grants 13JC140680 (to J.-G. L.) from the Committee of Science and Technology of Shanghai. ; This research was supported by grants 2013CB835100, 2015CB553502 (to J.-G. L.), 2013CB8351003(to L. X) from the Ministry of Science and Technology of China and by grants 81130087, 91232716 (to J.-G. L.) from the Foundation of National Natural Science of China and by grants 13JC140680 (to J.-G. L.) from the Committee of Science and Technology of Shanghai. ; This research was supported by grants 2013CB835100, 2015CB553502 (to J.-G. L.), 2013CB8351003(to L. X) from the Ministry of Science and Technology of China and by grants 81130087, 91232716 (to J.-G. L.) from the Foundation of National Natural Science of China and by grants 13JC140680 (to J.-G. L.) from the Committee of Science and Technology of Shanghai. ; This research was supported by grants 2013CB835100, 2015CB553502 (to J.-G. L.), 2013CB8351003(to L. X) from the Ministry of Science and Technology of China and by grants 81130087, 91232716 (to J.-G. L.) from the Foundation of National Natural Science of China and by grants 13JC140680 (to J.-G. L.) from the Committee of Science and Technology of Shanghai.
内容类型	期刊论文
源URL	[http://159.226.149.26:8080/handle/152453/11759]
专题	昆明动物研究所_动物模型与人类重大疾病机理重点实验室昆明动物研究所_学习记忆的分子神经机制
通讯作者	jgliu@mail.simm.ac.cn lxu@vip.163.com
作者单位	1.Department of Anatomy and Neurobiology, Collaborative Innovation Center for Brain Science, Tongji University School of Medicine, Shanghai 200092, China. 2.KIZ-SU Joint laboratory of Animal model and drug development, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China. 3.CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai 200031, China 4.These authors contributed equally to this work 5.Key Laboratory of Animal Models and Human Disease Mechanisms, and Laboratory of Learning and Memory, Kunming Institute of Zoology, the Chinese Academy of Science, Kunming 650223, Chin 6.Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science, Shanghai 201203, China. 7.Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China
推荐引用方式 GB/T 7714	Li M,Zhang L,Ju YY,et al. The small GTPase Rac1 contributes to extinction of aversive memories of drug withdrawal by facilitating GABA A receptor endocytosis in the vmPFC[J]. Journal of neuroscience,2017,():Epub ahead of print.
APA	Li M.,Zhang L.,Ju YY.,Wang WS.,jgliu@mail.simm.ac.cn lxu@vip.163.com.,...&Tang JX.(2017).The small GTPase Rac1 contributes to extinction of aversive memories of drug withdrawal by facilitating GABA A receptor endocytosis in the vmPFC.Journal of neuroscience,(),Epub ahead of print.
MLA	Li M,et al."The small GTPase Rac1 contributes to extinction of aversive memories of drug withdrawal by facilitating GABA A receptor endocytosis in the vmPFC".Journal of neuroscience .(2017):Epub ahead of print.