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

最成熟的表达活性依赖形式的机制 被称为长时程增强(LTP)和长时程抑制(LTD)的突触可塑性是 AMPA受体(AMPAR)进入或离开突触后膜。这 贩运被认为是由特定受体的身份以重要方式塑造的 树突棘中存在亚单位。AMPAR贩运的主导模式认为 这些亚基独特的C末端尾巴在将这些受体分选到 它们的预定目的地，无论是在表面膜中，特别是在 突触后膜，或在细胞内部位。最近，这种模式在一定程度上 对AMPAR不是按亚基组成排序的发现提出质疑，但 相反，LTP诱导的主要驱动因素是突触后特性的改变 密度和/或在树突棘体积中捕获亚基中的额外AMPAR 态度不分青红皂白。然而与此同时，之前的数据，包括我们自己的数据，强烈支持 突触后膜中特定的AMPAR亚单位对 LTP的诱导和定义的突触可塑性状态的规范。这笔赠款旨在 利用关于AMPA受体贩运的现有知识，在一系列新的 将我们已有的配对神经元电生理技术结合在一起的实验 使用我们最近获得的使用阵列层析成像来跟踪位置的功能进行记录 突触树突棘上的谷氨酸受体亚单位 经历了可塑性。我们将测试关于AMPA性质的相互竞争的假设 突触可塑性诱导过程中受体向突触后膜的转运。

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.