Actin Dynamics and Spine Remodeling in Ethanol-Induced Plasticity

乙醇诱导可塑性中的肌动蛋白动力学和脊柱重塑

• 批准号: 8461698
• 负责人: L Judson Chandler
• 金额: $ 31万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461698
• 关键词: 3-Dimensional; Actins; Alcohol dependence; Alcohol-Related Disorders; Alcoholism; Behavior; Biochemical; Brain; Brain region; Breathing; Cell model; Chronic; Complex; Computer software; Dendritic Spines; Development; Electrophysiology (science); Ethanol; Event; Excitatory Synapse; F-Actin; Fluorescent Dyes; Funding; G Actin; Glutamate Receptor; Glutamates; Goals; Homer protein; Image; In Vitro; Knockout Mice; Lead; Learning; Link; Measures; Membrane; Modeling; Modification; Molecular; Molecular Models; Morphology; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR2B NMDA receptor; Nature; Neurons; Nuclear Translocation; Physical Dependence; Play; Procedures; Process; Protein Dynamics; Research; Risk Factors; Role; Scaffolding Protein; Series; Shapes; Signal Transduction; Signaling Molecule; Site; Synapses; Synaptic plasticity; System; Testing; Three-Dimensional Imaging; Translations; Vertebral column; addiction; alcohol behavior; alcohol craving; alcohol exposure; alcohol related problem; alcohol response; alcohol seeking behavior; base; behavioral tolerance; chronic alcohol ingestion; density; drug of abuse; effective therapy; experience; gene gun; genetic regulatory protein; in vivo; in vivo Model; memory process; molecular modeling; mouse model; neurotransmission; novel; novel strategies; novel therapeutic intervention; postsynaptic; presynaptic density protein 95; response; scaffold; vapor

ABSTRACT Modifications of the size, shape, and number of spines is thought to be an important component of experience-dependent changes in neuronal circuits and may play an important role in the plasticity of addiction. Cellular models of activity-dependent plasticity have shown that changes in the subcellular localization of glutamate receptors is associated with a molecular reorganization of the postsynaptic density and alterations in spine morphology and/or density. The NMDA subtype of glutamate receptors play a central role in synaptic plasticity and are known targets of ethanol. Chronic ethanol consumption results in adaptive changes in neuronal function that manifest as tolerance, physical dependence and addiction. A potential adaptive mechanism we recently identified is the selective targeting of NR2B-containing NMDA receptors to the synapse. This increase is associated with, and dependent upon, a corresponding increase in the localization of the scaffolding protein PSD-95 at the postsynaptic density, and with an actin-dependent increase in the size of dendritic spines. These observations lead us to propose a molecular model for ethanol- induced plasticity at excitatory synapses in which increases in NR2B-containing NMDA receptors and PSD-95 at the postsynaptic density provides an expanded scaffolding platform for the recruitment and activation of signaling molecules that regulate spine actin dynamics, protein translation and synaptic plasticity. This renewal application will utilize biochemical, confocal imaging and electrophysiology procedures to test this hypothesis using well-defined in-vitro and in- vivo models of chronic ethanol exposure. The specific aims are to: (1) Test the hypothesis that modulation of spine actin dynamics is altered in response to chronic ethanol exposure; (2) Test the hypothesis that chronic ethanol exposure increases the size of dendritic spines; (3) Test the hypothesis that chronic ethanol exposure enhances the PSD-dependent association of translational-regulatory-proteins that modulate activity-dependent spine remodeling; (4) Test the hypothesis that the development of chronic ethanol-induced synaptic plasticity requires a PSD scaffolding-signaling complex that can support actin-based spine remodeling. This is a novel and timely proposal that is consistent with accumulating evidence that glutamatergic modulation of spine actin by the PSD plays a critical role in the plasticity of alcoholism and alcohol-related behaviors.

抽象的 刺的大小，形状和数量的修改被认为是重要组成部分 依赖经验的神经元电路变化，并可能在可塑性中发挥重要作用 成瘾。活性依赖性可塑性的细胞模型表明， 谷氨酸受体的亚细胞定位与分子重组有关 突触后密度和脊柱形态和/或密度的改变。 NMDA亚型 谷氨酸受体在突触可塑性中起着核心作用，并且是乙醇的已知靶标。 慢性乙醇消耗导致神经元功能的自适应变化，表现为 宽容，身体依赖和成瘾。我们最近的潜在自适应机制 确定的是将含NR2B的NMDA受体的选择性靶向突触。这 增加与相应的增加有关，并取决于 脚手架蛋白PSD-95在突触后密度下，并依赖肌动蛋白的增加 树突状刺的大小。这些观察结果使我们提出了乙醇的分子模型 兴奋性突触的诱导可塑性，其中含NR2B的NMDA受体增加 和突触后密度的PSD-95为该平台提供了一个扩展的脚手架平台 调节脊柱肌动蛋白动力学的信号分子的募集和激活 翻译和突触可塑性。此更新应用程序将利用生化，共识 成像和电生理程序，使用明确定义的体外和内部测试该假设 慢性乙醇暴露的体内模型。具体目的是：（1）检验以下假设。 脊髓肌动蛋白动力学的调节因慢性乙醇暴露而改变。 （2）测试 假设慢性乙醇暴露会增加树突状刺的大小。 （3）测试 假设慢性乙醇暴露增强了PSD依赖性关联 调节活动依赖性脊柱重塑的翻译调节蛋白； （4）测试 假设慢性乙醇引起的突触可塑性的发展需要PSD 可以支持基于肌动蛋白的脊柱重塑的脚手架信号复合体。这是一部小说， 及时的建议与累积证据表明脊柱谷氨酸能调节的证据一致 PSD的肌动蛋白在酒精中毒和与酒精相关的行为的可塑性中起关键作用。

项目成果

Inhibition of phosphodiesterase-4 decreases ethanol intake in mice.

• DOI: 10.1007/s00213-011-2290-8
• 发表时间: 2011-11
• 期刊: PSYCHOPHARMACOLOGY
• 影响因子: 3.4
• 作者: Hu, Wei;Lu, Tina;Chen, Alan;Huang, Ying;Hansen, Rolf;Chandler, L. Judson;Zhang, Han-Ting
• 通讯作者: Zhang, Han-Ting