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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：
10062396
负责人：
DION KAI DICKMAN
金额：
$ 11.11万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062396
关键词：
Acute Administrative Supplement Aging Alzheimer&apos s Disease Amino Acids C-terminal Chemosensitization Chronic Communication Complex DLG4 gene Data Defect Development Disease Drosophila genus Electrophysiology (science)Ensure Epilepsy Etiology Fragile X Syndrome Functional disorder Genes Genetic Genetic Screening Glutamate Receptor Glutamates Goals Growth Health Homologous Gene Human Image Invertebrates Mediating Modeling Molecular Motor Neurons Nature Nerve Degeneration Nervous system structure Neuromuscular Junction Peripheral Nervous System Pharmacology Process Rodent Role Schizophrenia Signal Induction Signal Transduction Sleep Structure Synapses Synaptic plasticity System Tail Testing Time Work autism spectrum disorder calmodulin-dependent protein kinase II density experience experimental study insight nervous system disorder neuromuscular neuropsychiatric disorder neuroregulation neurotransmitter release novel postsynaptic presynaptic quantum receptor function recruit scaffold synaptic function ubiquitin ligase

项目摘要

PROJECT SUMMARY Stable functionality in the nervous system is maintained despite the challenges associated with development, growth, experience, aging, and disease. This remarkable stability is controlled by potent and adaptive homeostatic signaling systems that sustain robust and reliable information transfer across synapses. Synapses are therefore critical substrates to achieve and maintain the homeostatic control of neural activity. Indeed, homeostatic synaptic plasticity is fundamental form of plasticity endowed at synapses in the central and peripheral nervous systems of invertebrates, rodents, and humans. Defects in homeostatic signaling contribute to the etiology of a variety of neurological diseases including epilepsy, Fragile X Syndrome, and neurodegeneration. However, the molecular mechanisms that induce and sustain homeostatic plasticity remain enigmatic. To understand synaptic dysfunction during disease states, we must first decipher the intercellular dialogue that controls homeostatic signaling. Our long-term goals are to define the mechanisms that achieve and maintain the homeostatic control of synaptic function in health and disease. Towards this end, we have pioneered forward genetic screens using electrophysiology that have discovered new genes and revealed fundamental mechanisms mediating homeostatic signaling at the Drosophila neuromuscular junction. At this model glutamatergic synapse, acute pharmacological inhibition or chronic genetic elimination of postsynaptic glutamate receptors (GluRs) triggers a retrograde signaling system in the postsynaptic compartment that precisely increases presynaptic neurotransmitter release to maintain stable synaptic strength. This process is referred to as Presynaptic Homeostatic Potentiation (PHP). Work from the Dickman lab and others have uncovered many presynaptic genes that converge on two key mechanisms that serve to increase neurotransmitter release and enable the expression of PHP. In addition, candidate retrograde signals have also been identified. In contrast to the emerging framework from which we now understand how enhanced presynaptic neurotransmitter release is controlled following PHP expression, almost nothing is known about the signaling system in the postsynaptic compartment that senses diminished GluR function and transforms this into tunable information transmitted to specific presynaptic compartments. Therefore, illuminating the nature of the postsynaptic induction mechanisms that initiate and maintain PHP will be the primary goal of this proposal. In this supplement, we propose to investigate the function of two newly identified postsynaptic genes, peflin and ALG2, in retrograde homeostatic signaling.

项目总结