Synaptic Homeostasis in Neocortical Neurons and Circuits

新皮质神经元和回路的突触稳态

• 批准号: 9111079
• 负责人: GINA G TURRIGIANO
• 金额: $ 40.45万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111079
• 关键词: Affinity; Attenuated; Autistic Disorder; Automobile Driving; Binding; Binding Proteins; Binding Sites; Biophysical Process; Defect; Diffuse; Dissociation; Drops; Endocytosis; Epilepsy; Equilibrium; Excitatory Synapse; GRIP1 gene; Health; Homeostasis; Image; Impairment; In Vitro; Lateral; Lead; Life; Measures; Modeling; Molecular; Monitor; Nature; Neurodegenerative Disorders; Neurons; Outcome; Physiological; Play; Process; Reagent; Resolution; Rodent; Role; Surface; Synapses; Synaptic plasticity; Testing; Visual; Visual Cortex; Weight; brain health; excitatory neuron; in vivo; interest; neocortical; nervous system disorder; neural circuit; postsynaptic; receptor; research study; response; restoration; scaffold; scale up; synaptic function; therapy design; tool; trafficking

 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.

 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，被认为对于维持神经回路发育中的稳定功能至关重要。突触缩放以正确的方向向上或向下“缩放”所有神经元的兴奋性突触强度，以稳定神经元放电率。突触权重的这些稳态调整在很大程度上是通过突触处含有 GluA2 的 AMPAR 突触积累的变化来实现的，并且似乎对给定神经元的所有兴奋性突触输入进行操作，以响应神经元自身放电的变化。尽管最近引起了极大的兴趣，但人们对突触缩放过程中 AMPAR 丰度这种稳态调节的分子和生物物理机制仍然知之甚少，并且这种突触缩放模型背后的许多假设（例如其全局性质）在很大程度上仍未经过测试。在本提案中，我们的目的是阐明在放大过程中导致突触 AMPAR 丰度增强的机制，并测试这种形式的可塑性作用于所有兴奋性输入以稳定体内神经元放电的想法。该提议是围绕最近观察到的，即 AMPAR 结合蛋白 GRIP1 对于放大过程中突触 AMPAR 丰度的调节增加至关重要，并且该过程需要 GRIP1 和 GluA2 之间的直接相互作用。在这里，我们建议通过使用各种尖端成像方法来确定（在生物物理水平上）GluA2-GRIP1 之间的这种调节相互作用如何驱动突触 AMPAR 丰度的增加。我们将测试两种替代模型：首先，GRIP1 与 AMPAR 一起运输到突触并增强受体的突触捕获，其次，GRIP1 增强修饰的 AMPAR 的突触传递，该修饰的 AMPAR 对突触支架具有增强的亲和力。此外，我们将使用通过这些体外研究产生的工具来选择性地破坏体内突触放大过程中的 AMPAR 运输，以探究完整新皮质回路内突触放大的机制和功能。