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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.

项目总结背景和目的：突触和回路具有强大的应激反应能力。他们利用体内平衡调节机制来维持生理上适当的水平突触输出。对突触可塑性的稳态形式的更好的了解应该会导致更好地了解当突触失去稳定性时发生的神经障碍。使用遗传以及模型果蝇神经肌肉接头(NMJ)突触的电生理方法，揭示了长期维持NMJ功能内稳所需的三个新因素。 ERD：两个位于肌肉中的酪氨酸激酶信号分子和一个磷脂酶C-β (PLCβ)分子驻留在神经元中。这项建议的目标是了解这些三个分子整合了细胞间的信号传递过程，以在整个生命过程中保持突触的稳定性。具体目标和研究设计：本项目有三个具体目标。前两个目标将描绘了每个相应的酪氨酸激酶如何驱动肌肉到神经的信号传递过程以稳定长时间发育过程中的突触活动。第三个目标将解决神经元如何可编程控制器β在突触处整合细胞-细胞信号，以自主控制神经元输出。每个目标将结合电生理学、遗传学、药理学、生物化学和突触成像。一等奖- 每个目标的RY测试都将挑战NMJ的功能-通常是通过抑制谷氨酸受体肌肉--然后通过电生理检查NMJ，检查它是否有适当的反应通过从神经元释放更多的谷氨酸来应对这一挑战。通过结合这种电生理学通过突触成像的方法，将有可能识别特定损伤的操作突触功能--与突触生长等其他参数相反。预期的结果是突触组织如何传递细胞-细胞信号以维持稳定的活动水平的详细模型。与健康相关：癫痫、共济失调和偏头痛等神经疾病与神经功能不稳定。因此，了解突触如何工作以维持脑部分子水平可能对具有潜在神经元不稳定性的疾病有深远的影响。然而，严格控制突触输出水平的细胞-细胞信号事件却知之甚少。遗传上易驯化的果蝇NMJ使用同位策略来稳定突触哺乳动物中枢共享的功能，如改变突触前钙内流的水平突触。利用NMJ提供的分子和遗传工具有望摆脱关于突触如何在整个生命中保持稳定功能的普遍保守的机制。