Single synapse analysis of synaptic plasticity by combining electrophysiology and array tomography

结合电生理学和阵列断层扫描的突触可塑性单突触分析

基本信息

批准号：
10059263
负责人：
Vernon Daniel MADISON
金额：
$ 56.57万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-23 至 2022-05-31
项目状态：
已结题

项目摘要

The most well-established mechanism for the expression of the activity-dependent forms of synaptic plasticity known as long-term potentiation (LTP) and long-term depression (LTD) is the trafficking of AMPA receptors (AMPARs) into or out of the postsynaptic membrane. This trafficking is believed to be shaped in important ways by the identity of the particular receptor subunits present in the dendritic spine. The dominant model of AMPAR trafficking has held that the unique C-terminal tails of these subunits play an important role in sorting these receptors to their intended destination, whether it be in the surface membrane, specifically in the postsynaptic membrane, or at an intracellular site. Recently that model has been partly challenged by findings that suggest that AMPARs are not sorted by subunit composition, but rather that the primary driver of LTP induction is a change in the properties of the postsynaptic density and/or in dendritic spine volume that captures additional AMPARs in a subunit indiscriminate manner. Yet at the same time, previous data, including our own, strongly support the idea that specific AMPAR subunits in the postsynaptic membrane are crucial for the induction of LTP and the specification of defined synaptic plasticity states. This grant seeks to leverage the existing knowledge about the trafficking of AMPA receptors in a new series of experiments that combines our established techniques of paired-neuron electrophysiological recordings with our more recently acquired ability to use array tomography to track the location of glutamate receptor subunits on dendritic spines of synapses specifically known to have undergone plasticity. We will test competing hypotheses concerning the nature of AMPA receptor trafficking into postsynaptic membranes during the induction of synaptic plasticity.

最完善的活性依赖形式表达机制突触可塑性称为长时程增强（LTP）和长时程抑制（LTD） AMPA 受体 (AMPAR) 进出突触后膜的运输。这据认为，贩运在重要方面是由特定受体的身份决定的存在于树突棘中的亚基。 AMPAR 贩运的主导模式认为这些亚基独特的 C 末端尾部在将这些受体分类到它们的预期目的地，无论是在表面膜中，特别是在突触后膜或细胞内位点。最近该模型已部分受到表明 AMPAR 并非按亚基组成排序的研究结果的挑战，而是相反，LTP 诱导的主要驱动因素是突触后特性的变化密度和/或树突棘体积，捕获亚基中的额外 AMPAR 不分青红皂白的方式。但与此同时，之前的数据，包括我们自己的数据，都强烈支持突触后膜中的特定 AMPAR 亚基对于 LTP 的诱导和定义的突触可塑性状态的规范。这笔赠款旨在在一系列新的研究中利用有关 AMPA 受体贩运的现有知识结合我们已建立的配对神经元电生理学技术的实验我们最近获得了使用阵列断层扫描来跟踪位置的能力的记录突触树突棘上谷氨酸受体亚基的分布特别已知经历了可塑性。我们将测试有关 AMPA 性质的相互竞争的假设在诱导突触可塑性期间受体转运到突触后膜。