阿片类物质戒断引起的负性情绪记忆是强迫性用药和戒断后复吸的重要原因。上海药物所刘景根课题组在之前的工作中发现杏仁核突触骨架重排(Actin重排)是吗啡戒断负性情绪记忆形成所必需的。在此基础上,课题组深入地研究了杏仁核突触骨架重排引起负性情绪记忆的分子机制。
研究工作发现杏仁核突触骨架重排能够使活性调节的突触骨架相关蛋白(Arc)向突触转运。突触上Arc水平增加能够促使突触膜上AMPA受体内吞。用突触骨架重排干扰剂抑制Arc蛋白向突触转运,或用慢病毒方法抑制杏仁核Arc蛋白表达,能够阻止AMPA受体内吞和干扰负性情绪记忆的形成。用小分子肽阻止突触膜上AMPA受体内吞可以抑制杏仁核LTD的产生和负性情绪记忆的产生。这些研究结果表明突触骨架重排依赖的Arc蛋白向突触转运和由此产生的AMPA受体内吞是吗啡戒断负性情绪记忆产生的关键分子事件。该研究结果已于8月29日发表在神经科学杂志(Journal of Neuroscience 32:12005-12017)上。
该研究工作是与昆明动物所徐林研究员课题组共同完成的。刘瑶博士和周启心博士是该工作的主要完成者。研究工作得到国家自然科学基金重点项目和科技部“973”项目的资助。(生物谷Bioon.com)
doi: 10.1523/JNEUROSCI.0871-12.2012
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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
Yao Liu, Qi-Xin Zhou, Yuan-Yuan Hou, Bin Lu, Chuan Yu, Jie Chen, Qing-Lan Ling, Jun Cao, Zhi-Qiang Chi, Lin Xu, and Jing-Gen Liu
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-GluR23Y, 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.