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：
10408706
负责人：
Jen Qian Pan
金额：
$ 60.51万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408706
关键词：
AMPA Receptors Address Behavioral Biological Process Biophysics Birth Brain C-terminal Calcineurin Calmodulin Calmodulin-Binding Proteins Characteristics Complex Data Defect Development Developmental Process Disease Electrophysiology (science)Equilibrium Event Excitatory Synapse Gene Targeting Generations Genes Genetic Glutamates Impairment Intervention Kinetics Link Mediating Mediator of activation protein Mental Retardation Mental disorders Molecular Molecular Target Morphology Mus N-Methyl-D-Aspartate Receptors NMDA receptor 2A NMDA receptor 2B Neurodevelopmental Disorder Pathway interactions Patients Pattern Pharmacology 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 base critical period developmental plasticity experience genetic manipulation knock-down mental development neural circuit neurogranin neuropsychiatric disorder novel paralogous gene postsynaptic receptor synaptic function synaptic pruning targeted treatment transmission process

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.

项目概要神经回路在发育过程中的最佳细化是一个高度受控的过程，关键取决于精神疾病的大量遗传证据特别指出了相关分子靶标的缺陷。兴奋性突触的经验依赖性发育可塑性，以及这种基本的失调该项目旨在阐明发育过程导致的各种神经精神疾病。经验在发育过程中塑造兴奋性突触功能连接的机制。我们发现，这个过程中的干扰如何破坏正常的发展轨迹。在其功能成熟的关键时期，小鼠初级视觉皮层（V1）的兴奋性突触维持 AMPA 受体介导的传输达到动态平衡，这种平衡需要神经颗粒素 (Ng)，一种对突触可塑性很重要的突触后钙调蛋白结合蛋白，与我们的初步研究表明，除了控制合并之外，精神分裂症和精神发育迟滞。 Ng 水平还控制 AMPA 受体进入缺乏 AMPA 受体（沉默）的突触和突触修剪 NMDA 受体亚基发育开关的时间，并改变 NMDA 受体亚基的磷酸化谱包括 NMDA 受体和 PSD-93/95 在内的几种突触后蛋白。该项目研究了这一假设。 Ng 水平通过改变兴奋性突触连接的经验依赖性重组 Ca/CaM 依赖性信号通路，包括 PP2B 和 NMDA 受体，使用病毒- 介导的基因操纵、突触生理学、通道生物物理学、形态分析和行为结果将阐明控制依赖于经验的细化的分子途径。发育过程中的兴奋性突触连接，将有助于确定药理学的潜在目标对患有神经发育障碍的患者进行干预。