Administrative Supplement (Diversity) to Molecular Mechanisms Governing the Homeostatic Control of Synaptic Strength

突触强度稳态控制分子机制的行政补充（多样性）

基本信息

批准号：
10523895
负责人：
DION KAI DICKMAN
金额：
$ 7.37万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10523895
关键词：
Acute Administrative Supplement Aging Alzheimer&apos s Disease Amino Acids Biological Models C-terminal Chemosensitization Chronic Communication Complex DLG4 gene Data Defect Development Disease Drosophila genus Electrophysiology (science)Ensure Epilepsy Etiology Fragile X Syndrome Functional Imaging Functional disorder Genes Genetic Genetic Screening Glutamate Receptor Glutamates Goals Growth Health Homologous Gene Image Impaired cognition Invertebrates Mediating Modeling Molecular Molecular Genetics Motor Neurons Nature Nerve Degeneration Nervous system structure Neuromuscular Junction Neurotransmitter Receptor Operating System Organism Pathway interactions Peripheral Nervous System Pharmacology Process Resolution Rodent Role Schizophrenia Seizures Signal Induction Signal Transduction Sleep Structure Synapses Synaptic plasticity System Tail Testing Time Work autism spectrum disorder calmodulin-dependent protein kinase II density excitotoxicity experience experimental study flexibility imaging approach innovation insight nervous system disorder neuromuscular neuropsychiatric disorder neuroregulation neurotransmission neurotransmitter release novel postsynaptic presynaptic quantum receptor function recruit scaffold synaptic function ubiquitin ligase ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Homeostatic signaling systems operate at synapses to enable flexible yet stable information transfer in the nervous system. Defects in homeostatic signaling contribute to seizures, excitotoxicity, cognitive decline, and neurodegeneration. Although much has been learned in recent years about the expression mechanisms synapses employ to counteract perturbations to neurotransmission, the pathways that rapidly initiate and chronically maintain homeostatic signaling remains poorly understood. Here, we propose to determine the induction mechanisms mediating homeostatic synaptic plasticity using the Drosophila neuromuscular junction as a unique and powerful model system. At this glutamatergic synapse, pharmacologic or genetic disruption to postsynaptic neurotransmitter receptors triggers a retrograde signaling system that leads to a compensatory increase in presynaptic glutamate release to maintain stable synaptic strength, referred to as presynaptic homeostatic potentiation (PHP). This process parallels similar phenomena observed in a variety of other organisms, including mammalian central synapses. We have recently discovered an E3 ubiquitin ligase adaptor that targets substrates in the postsynaptic compartment and enables retrograde homeostatic signaling. We propose to first identify and characterize postsynaptic targets of the homeostatic signaling system. Preliminary data suggests a key component of the postsynaptic density is necessary for retrograde homeostatic signaling. Next, we will define the induction mechanisms mediating the chronic expression of PHP and determine the role of CaMKII in this process. Finally, we will interrogate the pharmacological induction of PHP and test a hypothesis that trans-synaptic complexes mediate rapid retrograde homeostatic signaling. These studies will leverage a synergistic combination of molecular genetic, electrophysiological, and innovative functional imaging approaches at confocal, super resolution, and ultrastructural levels to determine the induction mechanisms that initiate and maintain retrograde homeostatic signaling. Together, these experiments will advance our understanding of the fundamental mechanisms that endow synapses with the capacity to sense perturbations to neurotransmission and adaptively modulate synaptic function to stabilize information transfer in the nervous system.

项目摘要稳态信号系统以突触运行，以启用灵活但稳定的信息在神经系统中转移。稳态信号的缺陷导致癫痫发作，兴奋性毒性，认知下降和神经退行性。虽然已经学到了很多近年来，关于表达机制的突触来抵消扰动神经传递，迅速启动并长期保持体内平衡的途径信号传导仍然很少了解。在这里，我们建议确定诱导机制使用果蝇神经肌肉连接作为一个独特而强大的模型系统。在此谷氨酸能突触，药理或遗传学突触后神经递质受体的破坏会触发逆行信号系统导致突触前谷氨酸释放的补偿性增加，以保持稳定的突触强度，称为突触前稳态增强（PHP）。这个过程类似在包括哺乳动物中央突触在内的许多其他生物中观察到的现象。我们最近发现了一个靶向突触后底物的E3泛素连接酶适配器隔室并启用逆行稳态信号传导。我们建议首先识别和表征体内稳态信号系统的突触后靶标。初步数据建议突触后密度的关键成分对于逆行稳态信号是必需的。接下来，我们将定义介导PHP慢性表达和的诱导机制确定CAMKII在此过程中的作用。最后，我们将询问药理诱导PHP并检验一个假说，即反性突触复合物介导快速逆行稳态信号传导。这些研究将利用分子遗传的协同组合，共凝聚，超级分辨率的电生理和创新功能成像方法，和超微结构水平以确定启动和维护的诱导机制逆行稳态信号传导。这些实验将共同提高我们的理解赋予突触具有扰动能力的基本机制神经传递和自适应调节突触功能，以稳定信息传递神经系统。