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: 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
• 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' 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

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.

项目摘要 神经系统中的稳定功能得以维持，尽管存在与以下相关的挑战： 发展、成长、经验、衰老和疾病。这种非凡的稳定性由以下因素控制： 有效和自适应的自我平衡信号系统，维持强大和可靠的信息 通过突触传递因此，突触是实现和维持突触的关键底物。 神经活动的自我平衡控制。事实上，稳态突触可塑性是 无脊椎动物中枢和外周神经系统突触的可塑性， 啮齿动物和人类。稳态信号传导的缺陷导致了多种疾病的病因， 神经系统疾病，包括癫痫、脆性X综合征和神经变性。然而，在这方面， 诱导和维持稳态可塑性的分子机制仍然是个谜。到 了解疾病状态下的突触功能障碍，我们必须首先破译细胞间的 控制自我平衡信号的对话。 我们的长期目标是确定实现和维持体内平衡的机制， 控制健康和疾病中的突触功能。为了实现这一目标， 利用电生理学进行基因筛选，发现了新的基因， 调节果蝇神经肌肉稳态信号的基本机制 交界处。在该模型中，急性药理学抑制或慢性遗传性突触 突触后谷氨酸受体（GluRs）的消除触发了一个逆行信号系统， 突触后隔室精确地增加突触前神经递质释放， 保持稳定的突触强度。这个过程被称为突触前稳态 增强（PHP）。Dickman实验室和其他人的工作已经揭示了许多突触前神经元 这些基因集中在两个关键机制上，这两个机制有助于增加神经递质的释放， 启用PHP的表达式。此外，还确定了候选逆行信号。 与我们现在理解的增强的突触前神经元 神经递质的释放是由PHP表达式控制的，几乎一无所知。 突触后隔室中的信号系统，其感知GluR功能减弱， 将其转化为可调节的信息传输到特定的突触前区室。 因此，阐明启动和激活突触后诱导机制的本质， 维护PHP将是本提案的主要目标。在本补充文件中，我们建议 研究两个新发现的突触后基因peflin和ALG2在逆行性突触形成中的功能。 稳态信号