Actin Dynamics and Spine Remodeling in Ethanol-Induced Plasticity

摘要 棘的大小、形状和数量的改变被认为是 经验依赖性的变化，在神经元回路，并可能发挥重要作用的可塑性 上瘾的人活动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谷氨酸受体的分子重组有关。 突触后密度和棘形态和/或密度的改变。NMDA亚型 谷氨酸受体在突触可塑性中起中心作用，并且是乙醇的已知靶点。 慢性乙醇消耗导致神经元功能的适应性变化，表现为 耐受、身体依赖和成瘾。最近，我们发现了一种潜在的适应机制， 确定的是含有NR 2B的NMDA受体选择性靶向突触。这 增加与局部化的相应增加相关联并且取决于局部化的相应增加。 支架蛋白PSD-95在突触后密度，并与肌动蛋白依赖性增加， 树突棘的大小这些观察使我们提出了乙醇的分子模型- 在兴奋性突触处诱导可塑性，其中含NR 2B的NMDA受体增加 突触后密度处的PSD-95为突触后密度提供了一个扩展的支架平台。 募集和激活调节棘肌动蛋白动力学的信号分子，蛋白质 翻译和突触可塑性。这种更新应用将利用生化，共聚焦 成像和电生理学程序来测试这一假设，使用明确的体外和体内 慢性乙醇暴露的体内模型。具体目的是：（1）检验假设， 脊髓肌动蛋白动力学的调制响应于慢性乙醇暴露而改变;（2）测试 假设慢性乙醇暴露增加树突棘的大小;（3）测试 假设慢性乙醇暴露增强了以下因素的PSD依赖性相关性 调节活动依赖性脊柱重塑的功能调节蛋白;（4）测试 假设慢性乙醇诱导的突触可塑性的发展需要PSD 支架信号复合物，可以支持肌动蛋白为基础的脊柱重塑。这是一部小说， 及时的建议，这是符合积累的证据表明，脊髓神经元的调制 在酒精中毒和酒精相关行为的可塑性中起着至关重要的作用。

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.