Actin Dynamics and Spine Remodeling in Ethanol-Induced Plasticity

摘要 脊柱的大小、形状和数量的改变被认为是 经验依赖的神经元回路改变，可能在可塑性中发挥重要作用 上瘾的人。依赖活动的可塑性的细胞模型表明， 谷氨酸受体的亚细胞定位与细胞内 突触后密度和脊柱形态和/或密度的变化。的NMDA子类型 谷氨酸受体在突触可塑性中起核心作用，也是乙醇的已知靶标。 慢性酒精摄入导致神经元功能的适应性改变，表现为 耐受性、身体依赖性和成瘾。一种潜在的适应机制，我们最近 已确定的是含有NR2B的NMDA受体选择性靶向突触。这 增加与本地化的相应增加相关联并依赖于 支架蛋白PSD-95在突触后密度，并随着肌动蛋白依赖的增加 树突棘的大小。这些观察结果使我们提出了乙醇的分子模型-- 兴奋性突触的可塑性，其中含有NR2B的NMDA受体增加 而突触后密度的PSD-95为 调节脊椎肌动蛋白动态的信号分子的招募和激活，蛋白质 翻译和突触可塑性。此续订应用程序将利用生化、共焦 成像和电生理学程序，以验证这一假说使用明确的体外和在- 慢性酒精暴露的活体模型。具体目的是：(1)检验假设 脊柱肌动蛋白动力学的调节因长期酒精暴露而改变；(2)测试 假设长期接触酒精会增加树突棘的大小；(3)测试 假设慢性酒精暴露增强了PSD依赖的关联 调节依赖活动的脊柱重塑的翻译调节蛋白；(4)测试 慢性乙醇诱导突触可塑性的发展需要PSD的假说 支架-信号复合体，可以支持基于肌动蛋白的脊柱重塑。这是一部小说和 及时的建议，与积累的证据一致，即脊柱的谷氨酸能调制 PSD的肌动蛋白在酒精中毒和酒精相关行为的可塑性中起着关键作用。

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.