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（由适用提供）：稳态突触缩放是一种重要形式的可塑性形式，认为对于在发展神经元电路中保持稳定功能至关重要。突触缩放“缩放”神经元的所有兴奋性突触强度的强度向上或向下沿正确的方向向上或向下，以稳定神经元的发射速率。这些突触重量的体内平衡调整很大程度上是通过突触下含有GLUA2 AMPAR的突触积累的变化来完成的，并且似乎在所有兴奋性突触输入上都在给定神经元上的所有兴奋性突触输入作用，以响应神经元自身发射的变化。尽管最近引起了极大的兴趣，但在突触缩放过程中可以稳态调整AMPAR抽象的分子和生物物理机制仍然很少了解，并且这种突触缩放模型（例如其全球性质）的许多假设仍然在很大程度上未被发过。在此提案中，我们旨在阐明导致扩展过程中合成AMPAR抽象增强的机制，并测试这种可塑性在所有令人兴奋的输入上以稳定体内神经元射击的想法。该建议是围绕或最近观察到的，即AMPAR结合蛋白GRIP1对于在扩展过程中调节的合成AMPAR抽象的增加至关重要，并且此过程需要GRIP1和GLUA2之间的直接相互作用。在这里，我们建议确定（在生物物理水平上）如何使用各种尖端成像方法（在生物物理水平上）这种调节的GLUA2-GRIP1之间的相互作用驱动突触AMPAR抽象的增加。我们将测试两个替代模型：首先，GRIP1运输与AMPAR一起进行突触，并增强对受体的合成捕获，其次，GRIP1增强了对突触支架具有增强亲和力的修饰AMPAR的合成递送。此外，我们将使用通过这些体外研究生成的工具在体内缩放突触扩展过程中有选择性地破坏AMPAR运输，以探测完整的新皮质回路中突触缩放的机制和功能。