Synaptic signals that drive the long-term maintenance of homeostatic neuroplasticity

驱动长期维持稳态神经可塑性的突触信号

基本信息

批准号：
10059270
负责人：
CARL ANDREW FRANK
金额：
$ 33.45万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10059270
关键词：
Acute Address Ataxia Biochemistry Biological Assay Biological Models Calcium Calcium Channel Cell Adhesion Molecules Cell Signaling Process Chronic Chronic Disease Development Disease Dissection Drosophila genus Drosophila melanogaster Electrophysiology (science)Epilepsy Event Feedback Fibroblast Growth Factor Fibroblast Growth Factor Receptors GTP-Binding Proteins Genetic Genetic Models Genetic Screening Glutamate Receptor Glutamates Goals Growth Health Homeostasis Homologous Gene Human Image Impairment Knowledge Lead Life Ligands Light Maintenance Mediating Metabotropic Glutamate Receptors Migraine Modeling Molecular Molecular Analysis Molecular Genetics Muscle Myasthenia NCAM1 gene Nerve Neural Cell Adhesion Molecules Neuromuscular Junction Neuronal Plasticity Neurons Outcome Output Pathway interactions Pharmacology Phospholipase Physiological Physiology Process Protein Tyrosine Kinase Proteins Proxy Research Research Design Shapes Signal Pathway Signal Transduction Signaling Molecule Sirolimus Synapses Synaptic plasticity System Testing Time Tissues Toxin Vesicle Work base biological adaptation to stress effective therapy fasciclin II flexibility improved insight intercellular communication nervous system disorder neuronal growth neurotransmission novel phospholipase C beta postsynaptic presynaptic programs protein-tyrosine kinase c-src quantum response stressor synaptic function therapy development tool

项目摘要

PROJECT SUMMARY Background and Objectives: Synapses and circuits possess a robust capacity for stress response. They employ homeostatic regulatory mechanisms to maintain physiologically appropriate levels of synaptic output. Improved knowledge about homeostatic forms of synaptic plasticity should lead to a better understanding of neurological disorders that occur when synapse stability is lost. Using genetic and electrophysiological approaches at the model Drosophila neuromuscular junction (NMJ) synapse, three new factors required for the long-term homeostatic maintenance of NMJ function were uncov- ered: two tyrosine kinase signaling molecules residing in the muscle and one phospholipase C-β (PLCβ) molecule residing in the neuron. The objective of this proposal is to understand how these three molecules integrate cell-cell signaling processes to maintain synapse stability throughout life. Specific Aims and Research Design: This project has three specific aims. The first two aims will delineate how each respective tyrosine kinase drives a muscle-to-nerve signaling process to stabilize synaptic activity over long periods of developmental time. The third aim will address how neuronal PLCβ integrates cell-cell signals at the synapse to autonomously control neuronal output. Each aim will combine electrophysiology, genetics, pharmacology, biochemistry, and synapse imaging. A prima- ry assay for each aim will be to challenge NMJ function – usually by inhibiting glutamate receptors in the muscle – and then to examine the NMJ by electrophysiology to check if it appropriately responds to that challenge by releasing more glutamate from the neuron. By combining this electrophysiological approach with synapse imaging it will be possible to identify manipulations that specifically impair synapse function – as opposed to other parameters, like synapse growth. The expected outcome is a detailed model of how synaptic tissues transmit cell-cell signals to maintain stable activity levels. Health Relatedness: Neurological disorders like epilepsy, ataxia, and migraine are associated with unstable neuronal function. Therefore, understanding how synapses work to maintain stability on a molecular level could have profound implications for disorders with underlying neuronal instabilities. Yet the cell-cell signaling events that tightly control levels of synaptic output are poorly understood. The genetically tractable Drosophila NMJ employs homoestatic strategies to stabilize synapse function – such as altering levels of presynaptic calcium influx – that are shared by mammalian central synapses. Taking advantage of the molecular and genetic tools offered by the NMJ promises to shed light on universally conserved mechanisms of how synapses maintain stable function throughout life.

项目概要背景和目标：突触和电路具有强大的应激反应能力。他们采用稳态调节机制来维持生理上适当的水平对突触可塑性稳态形式的了解应该会导致利用遗传更好地了解突触稳定性丧失时发生的神经系统疾病。果蝇神经肌肉接头（NMJ）突触模型的电生理学方法， NMJ 功能长期稳态维持所需的三个新因素尚未确定 ered：存在于肌肉中的两种酪氨酸激酶信号分子和一种磷脂酶 C-β (PLCβ) 分子驻留在神经元中。该提案的目的是了解这些分子是如何发挥作用的。三个分子整合细胞信号传导过程，以维持整个生命过程中的突触稳定性。具体目标和研究设计：该项目有三个具体目标，前两个目标是。描述每个酪氨酸激酶如何驱动肌肉到神经信号传导过程稳定第三个目标将解决神经元在长期发育过程中的突触活动。 PLCβ 在突触处整合细胞间信号来自主控制神经输出。将结合电生理学、遗传学、药理学、生物化学和突触成像。每个目标的试验都是挑战 NMJ 功能——通常是通过抑制体内的谷氨酸受体肌肉 – 然后通过电生理学检查 NMJ 以检查其是否有反应通过结合这种电生理学，从神经元中释放更多的谷氨酸来应对这一挑战。使用突触成像方法将有可能识别出专门损害神经元的操作突触功能——与其他参数相反，如突触生长。突触组织如何传递细胞间信号以维持稳定的活动水平的详细模型。健康相关性：癫痫、共济失调和偏头痛等神经系统疾病与因此，了解突触如何维持神经功能的稳定性。分子水平可能对具有潜在神经不稳定的疾病产生深远的影响。然而，人们对严格控制突触输出水平的细胞间信号传导事件知之甚少。遗传上易控制的果蝇 NMJ 采用稳态策略来稳定突触功能 - 例如改变突触前钙流入的水平 - 这是哺乳动物中枢所共有的利用 NMJ 提供的分子和遗传工具有望摆脱突触。揭示突触如何在整个生命过程中保持稳定功能的普遍保守机制。