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Imaging Synaptic Transmission of Individual Active Zones

单个活动区的突触传递成像

基本信息

批准号：
10542793
负责人：
J. TROY LITTLETON
金额：
$ 38.5万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10542793
关键词：
Action Potentials Acute Address Biological Models Biology Biosensor Brain Brain Diseases Calcium Channel Chronic Communication Complement Data Date of birth Development Docking Drosophila genus Elements Event Foundations Generations Glutamate Receptor Glutamates Heterogeneity Image Individual Investigation Link Maps Mental disorders Methods Molecular Molecular Profiling Motor Neurons Neuromuscular Junction Neurons Pathway interactions Population Postsynaptic Membrane Probability Process Property Proteins Recording of previous events Research Resolution Signal Transduction Site Structural Protein Synapses Synaptic Transmission Synaptic Vesicles Synaptic plasticity Therapeutic Time Variant density experimental study human disease imaging approach insight intravital imaging light microscopy nervous system disorder neural circuit neurotransmitter release presynaptic presynaptic neurons reconstruction segregation sensor serial imaging synaptic function synaptogenesis tool trafficking vesicular release voltage

项目摘要

We propose to use Drosophila as a model system for determining how neurotransmitter release and plasticity are regulated at individual active zones (AZs). Synaptic vesicle fusion occurs through a highly probabilistic process, often with only a small percent of action potentials triggering release from individual AZs. Although AZs largely share the same complement of proteins, release probability (Pr) is highly variable across different neurons and between AZs of the same neuron. Indeed, some AZ-specific proteins are non-uniformly distributed, and the molecular composition of AZs can undergo rapid changes. To date, Ca2+ channel abundance and Ca2+ influx have been most strongly linked to Pr heterogeneity, though other factors are likely to contribute as well. The Drosophila neuromuscular junction (NMJ) has emerged as a robust model system to characterize determinants of Pr. By transgenically expressing GCaMP Ca2+ sensors targeted to the postsynaptic membrane, single synaptic vesicle fusion events at individual AZs can be imaged by following spatially localized Ca2+ influx induced upon glutamate receptor opening. This enabled us to generate Pr maps for evoked and spontaneous fusion for all AZs, leading to the surprising observation that AZs formed by a single motor neuron have a heterogeneous distribution of Pr, with neighboring AZs often showing ~50-fold differences in strength. In addition, 10% of the AZ population supports only spontaneous release, while another 15% are functionally silent for both evoked and spontaneous fusion. In this proposal, we will determine how Pr is uniquely set for individual AZs and what molecular, structural, and developmental variables govern Pr heterogeneity. We will also examine how presynaptic Ca2+ channels traffic to and between AZs, and how plasticity alters these processes. These approaches should provide new insights into the complement of AZ proteins that functionally regulate Pr, spontaneous release, and silent synapses, and how they cooperate with presynaptic Ca2+ channels to set Pr across a functionally diverse set of AZs. Disruptions of synapse formation and function have been linked to a host of neurological and psychiatric diseases, reflecting the importance of these processes. The experiments described in this proposal will generate new insights into important elements that define the strength and release mode of individual AZs at an unprecedented resolution.

我们建议使用果蝇作为模型系统来确定神经递质是如何释放的