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.

项目摘要背景和目标：突触和电路具有强大的压力反应能力。他们采用稳态调节机制来维持身体适当的水平突触输出。提高了关于突触可塑性体内稳态形式的知识，应导致在失去突触稳定性时会更好地理解发生的神经系统疾病。使用遗传以及模型果蝇神经肌肉连接（NMJ）突触的电生理方法，长期维持NMJ功能所需的三个新因素是不验证的 ERED：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）驻留在神经元中的分子。该提议的目的是了解这些三个分子整合了细胞 - 细胞信号传导过程，以维持一生的突触稳定性。具体目的和研究设计：该项目具有三个特定目标。前两个目标将描述每个相对酪氨酸激酶如何驱动肌肉到神经信号传导过程以稳定长期发育时间的突触活动。第三个目标将解决神经元如何 PLCβ会在突触时整合细胞电信号，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。 Prima- 每个目标的RY分析将是挑战NMJ功能 - 通常通过抑制谷氨酸接收器肌肉 - 然后通过电生理检查NMJ，以检查是否适当响应通过从神经元中释放更多的谷氨酸来挑战。通过结合该电生理学突触成像的方法可以识别出特别损害的操作突触功能 - 与其他参数相反，例如突触生长。预期的结果是突触组织如何传输细胞细胞信号以保持稳定活性水平的详细模型。健康相关性：癫痫，共济失调和偏头痛等神经系统疾病与不稳定的神经元功能。因此，了解突触如何工作以保持稳定性分子水平可能对具有潜在神经元不稳定性的疾病具有深远的影响。然而，严格控制突触输出水平的细胞 - 细胞信号事件知之甚少。通常可拖延的果蝇NMJ员工稳定突触的均匀策略功能 - 例如改变突触前钙影响的水平 - 由哺乳动物中央共享突触。利用NMJ提供的分子和遗传工具有望放弃关于突触如何在一生中保持稳定功能的普遍配置机制的启示。