Experience-Dependent Reorganization of Excitatory Synapse Connectivity

兴奋性突触连接的经验依赖性重组

基本信息

批准号：
10668412
负责人：
Jen Qian Pan
金额：
$ 61.01万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668412
关键词：
AMPA Receptors Acceleration Address Behavioral Biological Process Biophysics Birth Brain C-terminal Calcineurin Calmodulin Calmodulin-Binding Proteins Characteristics Complex DLG4 gene Data Defect Development Developmental Process Disease Electrophysiology (science)Equilibrium Event Excitatory Synapse Gene Targeting Generations Genes Genetic Glutamates Impairment Intervention Kinetics Link Mediating Mediator Mental Retardation Mental disorders Molecular Molecular Target Morphology Mus N-Methyl-D-Aspartate Receptors Neurodevelopmental Disorder Pathway interactions Patients Pattern Phosphorylases Phosphorylation Phosphorylation Site Physiology Process Property Proteins Proteomics Resolution Risk Factors Role Scaffolding Protein Schizophrenia Shapes Signal Pathway Signal Transduction Synapses Synaptic Transmission Synaptic plasticity Therapeutic Variant Virus Vision Visual Cortex area striata critical period developmental plasticity experience genetic manipulation knock-down mental development neural circuit neurogranin neuropsychiatric disorder novel paralogous gene pharmacologic postsynaptic receptor synaptic function synaptic pruning targeted treatment transmission process

AMPA Receptors Acceleration Address Behavioral Biological Process Biophysics Birth Brain C-terminal Calcineurin Calmodulin Calmodulin-Binding Proteins Characteristics Complex DLG4 gene Data Defect Development Developmental Process Disease Electrophysiology (science)Equilibrium Event Excitatory Synapse Gene Targeting Generations Genes Genetic Glutamates Impairment Intervention Kinetics Link Mediating Mediator Mental Retardation Mental disorders Molecular Molecular Target Morphology Mus N-Methyl-D-Aspartate Receptors Neurodevelopmental Disorder Pathway interactions Patients Pattern Phosphorylases Phosphorylation Phosphorylation Site Physiology Process Property Proteins Proteomics Resolution Risk Factors Role Scaffolding Protein Schizophrenia Shapes Signal Pathway Signal Transduction Synapses Synaptic Transmission Synaptic plasticity Therapeutic Variant Virus Vision Visual Cortex area striata critical period developmental plasticity experience genetic manipulation knock-down mental development neural circuit neurogranin neuropsychiatric disorder novel paralogous gene pharmacologic postsynaptic receptor synaptic function synaptic pruning targeted treatment transmission process

展开

项目摘要

Project Summary Optimal refinement of neural circuits during development is a highly controlled process that depends critically on experience. Ample genetic evidence in mental disorders points specifically to defects in molecular targets related to experience-dependent developmental plasticity of excitatory synapses, and dysregulation of this fundamental developmental process results in a variety of neuropsychiatric diseases. This project seeks to elucidate mechanisms by which experience sculpts the functional connection of excitatory synapses during development and how perturbations in this process can derail the normal developmental trajectory. We found that during the critical period of their functional maturation, excitatory synapses of the mouse primary visual cortex (V1) maintain a dynamic equilibrium in their AMPA receptor-mediated transmission. This equilibrium requires neurogranin (Ng), a postsynaptic calmodulin-binding protein important for synaptic plasticity, which is has been implicated in schizophrenia and mental retardation. Our preliminary studies show that in addition to controlling incorporation of AMPA receptors into AMPA receptor-lacking (silent) synapses and synaptic pruning, Ng levels also control the timing of the developmental switch in NMDA receptor subunits, and change the phosphorylation profiles of several post synaptic proteins including NMDA receptor and PSD-93/95. This project investigates the hypothesis that Ng levels influence the experience-dependent reorganization of excitatory synaptic connectivity by altering Ca/CaM-dependent signaling pathways, including PP2B and NMDA receptors, using a combination of virus- mediated gene manipulation, synaptic physiology, channel biophysics, morphological analysis, and behavioral interrogation. The results will elucidate the molecular pathways governing experience-dependent refinement of excitatory synaptic connectivity during development and will help to identify potential targets for pharmacologic interventions in patient with neurodevelopmental disorders.

项目摘要开发过程中神经回路的最佳改进是一个高度控制的过程，取决于经验。精神疾病中充分的通用证据特别是与分子靶标的缺陷有关兴奋性突触的经验依赖性的发展可塑性和这种基本的失调发展过程导致各种神经精神疾病。这个项目看到以阐明经验在开发过程中造成兴奋性突触的功能连接的机制以及此过程中的扰动如何使正常的发育轨迹脱轨。我们发现在功能成熟的关键时期，小鼠初级视觉皮层（V1）的兴奋性突触保持 AMPA受体介导的传输中的动态平衡。这种平衡需要神经素（NG），突触后钙调蛋白结合蛋白对突触可塑性很重要，这与精神分裂症和智力低下。我们的初步研究表明，除了控制基础架构外 AMPA受体进入AMPA受体堆积（无声）突触和突触修剪，NG水平也控制 NMDA受体亚基中发育开关的时机，并更改几个帖子包括NMDA受体和PSD-93/95，包括突触蛋白。该项目调查了假设 NG水平通过改变而影响兴奋性突触连通性的经验依赖性重组 CA/CAM依赖性信号通路，包括PP2B和NMDA接收器，使用病毒 - 介导的基因操纵，突触生理，通道生物物理学，形态分析和行为审讯。结果将阐明有关经验依赖性改进的分子途径开发过程中的兴奋性突触连通性，将有助于确定药物的潜在靶标神经发育障碍患者的干预措施。