title: Actin polymerization-dependent increase in synaptic Arc/Arg3.1 expression in the amygdala is crucial for the expression of aversive memory associated with drug withdrawal.
abstract: Aversive memories associated with drug withdrawal may contribute to persistent drug seeking. Molecular mechanisms that are critical for aversive memory formation have yet to be elucidated. Recently, we showed in a rat conditioned place aversion (CPA) model that synaptic actin polymerization in the amygdala were required for aversive memory information. Here, we demonstrated that actin polymerization within the amygdala triggered transportation of activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) into amygdalar synapses. Increased synaptic Arc/Arg3.1 expression contributed to aversive memory formation by regulating synaptic AMPA receptor (AMPAR) endocytosis, as in vivo knockdown of amygdalar Arc/Arg3.1 with Arc/Arg3.1-shRNA prevented both AMPAR endocytosis and CPA formation. We also demonstrated that conditioned morphine withdrawal led to induction of LTD in the amygdala through AMPAR endocytosis. We further demonstrated that Arc/Arg3.1-regulated AMPAR endocytosis was GluR2 dependent, as intra-amygdala injection of Tat-GluR2(3Y), a GluR2-derived peptide that has been shown to specifically block regulated, but not constitutive, AMPAR endocytosis, prevented AMPAR endocytosis, LTD induction, and aversive memory formation. Therefore, this study extends previous studies on the role of actin polymerization in synaptic plasticity and memory formation by revealing the critical molecular events involved in aversive memory formation as well as LTD induction, and by showing that Arc/Arg3.1 is a crucial mediator for actin polymerization functions, and, thus, underscores the unknown details of how actin polymerization mediates synaptic plasticity and memory.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Liu
authors.forename: Qi-Xin
authors.initials: QX
authors.lastname: Zhou
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Hou
authors.forename: Bin
authors.initials: B
authors.lastname: Lu
authors.forename: Chuan
authors.initials: C
authors.lastname: Yu
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Qing-Lan
authors.initials: QL
authors.lastname: Ling
authors.forename: Jun
authors.initials: J
authors.lastname: Cao
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Chi
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Jing-Gen
authors.initials: JG
authors.lastname: Liu
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D001362:Avoidance Learning; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000172:deficiency; D004705:Endocytosis / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008568:Memory / Q000502:physiology*; D009020:Morphine / Q000009:adverse effects; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000172:deficiency; D009473:Neuronal Plasticity / Q000235:genetics; D058105:Polymerization; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; C092069:activity regulated cytoskeletal-associated protein; D009020:Morphine