How discrete homeostatic signals stabilize synapse function across time

离散稳态信号如何随时间稳定突触功能

基本信息

批准号：
10706581
负责人：
CARL ANDREW FRANK
金额：
$ 38.97万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-19 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10706581
关键词：
Acute Address Ataxia Binding Biochemistry Biological Models Bone Morphogenetic Proteins Buffers Calcium Chaperone Gene Chemosensitization Chronic Data Depressed mood Development Disease Drosophila genus Drosophila melanogaster Electrophysiology (science)Engineering Epilepsy Event Exhibits Fibroblast Growth Factor Receptors Gene Mutation Genes Genetic Genetic Diseases Genetic Models Genetic Screening Glutamate Receptor Goals Health Homeostasis Hour Image Impairment Knowledge Life Link Maintenance Mediating Methods Migraine Modality Modeling Molecular Molecular Chaperones Monitor Motor Neurons Muscle Nerve Nerve Degeneration Neurodegenerative Disorders Neurodevelopmental Disorder Neurologic Neuromuscular Junction Neuronal Plasticity Neurons Neurosciences Neurotransmitter Receptor Outcome Output Pathway interactions Peptide Signal Sequences Pharmacology Phase Physiological Process Property Puncture procedure Research Research Design Science Semaphorins Signal Induction Signal Pathway Signal Transduction Signaling Molecule Sirolimus Spermine Stress Synapses Synaptic plasticity System Testing Time Work effective therapy follow-up improved inhibitor loss of function nervous system disorder neurotransmission pharmacologic presynaptic receptor function synaptic function tool transmission process

项目摘要

PROJECT SUMMARY Background and Objectives: Synapses and circuits possess a robust capacity for keeping their outputs stable. Using the Drosophila melanogaster neuromuscular junction (NMJ) as a model synapse, many labs have recently identified dozens of signaling molecules and processes that stabilize synapse function through a non-Hebbian form of homeostatic neuroplasticity called presynaptic homeostatic potentiation (PHP). These findings offer a rich reservoir for discovery science, but at this point we have little understanding of how dozens of discrete homeostatic signaling molecules integrate into coherent system that stabilizes synapse function over time. The objective of this proposal is to solve that problem combining genetics, pharmacology, imaging, biochemistry, and electrophysiology. Ultimately, improved knowledge about homeostatic forms of synaptic plasticity could lead to a better understanding of neurological disorders that occur when synapse stability is lost. Specific Aims and Research Design: This project has two specific aims. We know that PHP at the Drosophila NMJ can be acutely induced in minutes and then chronically maintained for days. The first aim is to define a sequence of events that occurs during the opening minutes of PHP induction. For this aim, we take advantage of a serendipitous finding from a genetic screen: impaired chaperone function in the muscle slows PHP signaling. Using this genetic tool we will delineate an order of processes that occurs as the muscle signals to the nerve and potentiates release. For the second aim, we developed a new pharmacological approach to monitor the transition periods between induction, acute expression, and long-term maintenance of PHP. We will apply this new method to characterize about 25 known genetic conditions that impact the sustained maintenance of PHP. We expect to define distinct PHP signaling modalities. Between our aims, the expected outcome is a model of how a synapse can sustain homeostatic function by integrating multiple signals across phases of time. Health Relatedness: Neurological disorders like epilepsy, ataxia, and migraine are associated with unstable neuronal function. Understanding how synapses work to maintain stability on a molecular level could have pro- found implications for disorders with underlying neuronal instabilities. Yet the signaling events that tightly control levels of synaptic output are poorly understood. The 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：突触和电路具有保持输出稳定的强大能力。许多实验室最近使用果蝇神经肌肉接头（NMJ）作为模型突触鉴定了数十种通过非赫布稳定突触功能的信号分子和过程这些发现提供了一种称为突触前稳态增强（PHP）的稳态神经可塑性。发现科学的丰富储库，但目前我们对数十个离散的如何稳态信号分子整合到连贯系统中，随着时间的推移稳定突触功能。该提案的目的是结合遗传学、药理学、成像、生物化学和最终，对突触可塑性稳态形式的了解可能会导致更好地了解突触稳定性丧失时发生的神经系统疾病。具体目标和研究设计：我们知道果蝇中的 PHP 有两个具体目标。 NMJ 可以在几分钟内急性诱导，然后长期维持数天。第一个目标是定义一个 NMJ。为了实现这一目标，我们利用了 PHP 入门课程开始时发生的一系列事件。基因筛查的一个偶然发现：肌肉中的伴侣功能受损会减慢 PHP 信号传导。使用这种遗传工具，我们将描绘肌肉向神经发出信号时发生的过程顺序对于第二个目标，我们开发了一种新的药理学方法来监测。 PHP 的诱导、急性表达和长期维持之间的过渡期。新方法描述了影响 PHP 持续维持的约 25 种已知遗传条件。我们期望定义不同的 PHP 信号模式。在我们的目标之间，预期结果是一个模型。突触如何通过跨时间阶段整合多个信号来维持稳态功能。健康相关性：癫痫、共济失调和偏头痛等神经系统疾病与不稳定有关了解突触如何在分子水平上维持稳定性可能有利于发现了对具有潜在神经不稳定的疾病的影响，但信号事件却严格控制。对于易驯化的果蝇 NMJ 采用稳态策略，人们对突触输出的水平知之甚少。稳定突触功能——例如改变突触前钙流入的水平——这是由利用 NMJ 提供的分子和遗传工具有望。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。