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）

• 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
• 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' 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

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 稳态信号系统在突触上运作，使信息灵活而稳定 在神经系统中的转移。体内平衡信号的缺陷导致癫痫发作， 兴奋性毒性、认知衰退和神经变性。虽然我们已经从 最近几年关于突触用来抵消干扰的表达机制， 神经传递，快速启动和长期维持稳态的途径 信号传导仍然知之甚少。在这里，我们建议确定诱导机制 使用果蝇神经肌肉接头作为调节稳态突触可塑性的方法 独特而强大的模型系统。在这个神经元突触，药理学或遗传学 突触后神经递质受体的破坏触发了一个逆行信号系统， 导致突触前谷氨酸释放的代偿性增加，以维持稳定的突触 突触前稳态增强（PHP）。这个过程类似于 在许多其他生物体中观察到的现象，包括哺乳动物的中央突触。我们 最近发现了一种E3泛素连接酶接头，它靶向突触后基质， 隔室并实现逆行稳态信号传导。我们建议首先确定和 表征稳态信号系统的突触后靶点。初步数据提示 突触后密度的一个关键成分是逆行稳态信号传导所必需的。 接下来，我们将定义介导PHP慢性表达的诱导机制， 确定CaMKII在此过程中的作用。最后，我们将询问药理学 诱导PHP并检验跨突触复合物介导快速逆行假说 稳态信号这些研究将利用分子遗传学， 电生理学和创新的功能成像方法，共焦，超分辨率， 和超微结构水平，以确定诱导机制，启动和维持 逆行稳态信号这些实验将共同推进我们对 赋予突触感知扰动能力的基本机制， 神经传递和适应性调节突触功能，以稳定信息传递， 神经系统