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Axonal FMRP in Synaptic Development

突触发育中的轴突 FMRP

基本信息

批准号：
10672424
负责人：
Yuan Wang
金额：
$ 37.98万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672424
关键词：
Acute Adhesions Axon Axonal Transport Behavioral Brain Calcium Cell Adhesion Molecules Cells Chick Embryo Chickens Cues Development Elements Embryo Evolution Exocytosis FMR1 Fragile X Syndrome Functional Imaging Functional disorder Generations Glutamates Goals Human Image Impairment Inherited Intellectual functioning disability Knowledge Location Mammals Mediating Molecular Neurodevelopmental Disorder Outcome Pathway interactions Pharmaceutical Preparations Phenotype Physiological Presynaptic Terminals Probability Process Protein Deficiency Proteins Publishing RNA-Binding Proteins Regulation Resolution Role Synapses Synaptic Transmission Synaptic Vesicles Synaptic plasticity System Testing Time Traction Translations Up-Regulation Vesicle adhesion receptor autism spectrum disorder functional loss genetic approach genetic manipulation in vivo knockout animal neural circuit neuropathology neurotransmission neurotransmitter release novel novel therapeutics postsynaptic presynaptic presynaptic neurons prevent protein expression protein function sensor structural imaging synaptogenesis synaptotagmin therapeutic candidate therapy development

项目摘要

Project Summary This project will address the question of how abnormal synaptic development emerges in neurodevelopmental disorders. Our overall hypothesis is that disorganized synaptic adhesion and delayed functional assembly of synaptic vesicles (SVs) impair the formation and physiological maturation of presynaptic terminals, which triggers subsequent developmental deficits in synaptic connectivity and function. We will test this hypothesis in Fragile X syndrome (FXS), a leading inheritable form of autism and intellectual disability caused by functional loss of Fragile X mental retardation protein (FMRP). Experimental observations will utilize the evolutionally conserved endbulb terminals that are readily accessible for in vivo cell-autonomous characterizations in chicken embryos. We will pursue two specific aims to test several important hypotheses derived from our preliminary studies. · In Specific Aim 1, we will determine the role of FMRP-regulated synaptic adhesion in presynaptic terminal formation. We hypothesize that axonal FMRP promotes terminal formation, stabilization, and selective retraction through developmentally profiled synaptic adhesion. To test this hypothesis, we will use cell-group specific and temporally-controlled genetic manipulations combined with in vivo live imaging to identify the exact actions of FMRP-mediated axon transport vs. protein translation in dynamic terminal turnover. We will also identify FMRP-regulated synaptic adhesion elements in developing terminals and assess the effects of correcting these elements on FMRP loss-induced presynaptic and axon alterations. · In Specific Aim 2, we will determine the role of FMRP-regulated synaptotagmin (Syt) in functional maturation of presynaptic terminals. Syt1/2 are primary calcium sensors on SVs that trigger vesicle fusion and neurotransmitter release. We hypothesize that FMRP regulates presynaptic functional maturation by controlling the timely upregulation of Syt2 in nascent terminals. To test this hypothesis, we will determine the effects of expressing Syt2 on FMRP loss-induced deficits in SV activity, presynaptic protein machinery, and glutamate release. We will also determine the interplay between synaptic adhesion regulation and SV assembly under FMRP control using rescue studies. Together, these results will identify an origin of defective synaptic phenotypes, a hallmark of neurodevelopmental disorders. This knowledge is of vital importance because it will help establish a sensitive time window and identify novel therapeutic candidates for preventing, or at least reducing, the progress of synaptic deficits in FXS and other neurodevelopmental disorders.

项目总结