Synaptic Homeostasis in Neocortical Neurons and Circuits

 描述（由申请人提供）：稳态突触缩放是可塑性的一种重要形式，被认为是在发育神经回路中维持稳定功能所必需的。突触缩放将神经元的所有兴奋性突触强度的强度在正确的方向上向上或向下“缩放”，以稳定神经元的放电速率。突触权重的这些稳态调整在很大程度上是通过突触处含GluA 2的AMPAR的突触积累的变化来实现的，并且似乎响应于神经元自身放电的变化而对给定神经元上的所有兴奋性突触输入进行操作。尽管最近很大的兴趣，分子和生物物理机制，使这种稳态调整的AMPAR丰度在突触缩放仍然知之甚少，许多假设的基础上，这种模型的突触缩放（如其全球性质）仍然在很大程度上未经测试。在这项提案中，我们的目标是照亮的机制，导致增强突触AMPAR丰度在按比例放大，并测试的想法，这种形式的可塑性作用于所有兴奋性输入，以稳定神经元在体内放电。这个建议是建立在或最近的观察，AMPAR结合蛋白GRIP 1是必不可少的调节增加突触AMPAR丰度在放大过程中，这一过程需要GRIP 1和GluA 2之间的直接相互作用。在这里，我们提出了确定如何（在生物物理水平），这种调节GluA 2-GRIP 1之间的相互作用驱动突触AMPAR丰度的增加，通过使用各种尖端成像方法。我们将测试两种替代模型：首先，GRIP 1与AMPAR一起沿着输送到突触，并增强受体的突触捕获，其次，GRIP 1增强修饰的AMPAR的突触递送，这些修饰的AMPAR对突触支架的亲和力增强。此外，我们将使用我们通过这些体外研究产生的工具，在体内突触放大过程中选择性地破坏AMPAR运输，以探索完整的新皮层回路内突触放大的机制和功能。

 DESCRIPTION (provided by applicant): Homeostatic synaptic scaling is an important form of plasticity thought to be essential for maintaining stable function in developing neural circuits. Synaptic scaling "scales" the strength of all of a neuron's excitatory synaptic strengths up or down in the correct direction to stabilize neuronal firing rates. These homeostatic adjustments in synaptic weights are accomplished in large part through changes in the synaptic accumulation of GluA2-containing AMPAR at synapses, and appear to operate on all excitatory synaptic inputs onto a given neuron in response to changes in the neuron's own firing. Despite great recent interest, the molecular and biophysical mechanisms that enable this homeostatic adjustment of AMPAR abundance during synaptic scaling are still poorly understood, and many of the assumptions underlying this model of synaptic scaling (such as its global nature) remain largely untested. In this proposal we aim to illuminate the mechanisms that lead to enhanced synaptic AMPAR abundance during scaling up, and to test the idea that this form of plasticity acts on all excitatory inputs to stabilize neuronal firing in vivo. This proposal is built around or recent observation that the AMPAR-binding protein GRIP1 is essential for the regulated increase in synaptic AMPAR abundance during scaling up, and that this process requires direct interactions between GRIP1 and GluA2. Here we proposed to determine how (at the biophysical level) this regulated interaction between GluA2-GRIP1 drives an increase in synaptic AMPAR abundance, by using a variety of cutting edge imaging approaches. We will test two alternative models: first, that GRIP1 traffics to synapses along with AMPAR and enhances synaptic capture of the receptor, and second, that GRIP1 enhances synaptic delivery of modified AMPAR that have an enhanced affinity for synaptic scaffolds. Further, we will use the tools we have generated through these in vitro studies to selectively disrupt AMPAR trafficking during synaptic scaling up in vivo, in order to probe the mechanism and function of synaptic scaling within intact neocortical circuits.