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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：
10088612
负责人：
CARL ANDREW FRANK
金额：
$ 6.51万
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/10088612
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