Molecular Mechanisms Governing the Homeostatic Control of Synaptic Strength

突触强度稳态控制的分子机制

• 批准号: 9195756
• 负责人: DION KAI DICKMAN
• 金额: $ 36.09万
• 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 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9195756
• 关键词: Acute; Autistic Disorder; Autoreceptors; Biological Models; Bipolar Disorder; Calcium; Chemosensitization; Complex; Defect; Development; Disease; Drosophila genus; Electrophysiology (science); Engineering; Ensure; Epilepsy; Etiology; Extracellular Domain; FMR1; Family; Foundations; Fragile X Syndrome; Functional disorder; Genes; Genetic; Genetic Screening; Glutamate Receptor; Goals; Growth; Health; Homeostasis; Human; Image; Impairment; Integral Membrane Protein; Intellectual functioning disability; Invertebrates; Kainic Acid Receptors; Knowledge; Lead; Link; Mental disorders; Microscopy; Molecular; Muscle; Nervous System Physiology; Nervous system structure; Neuromuscular Junction; Neurons; Neurophysiology - biologic function; Neurotransmitter Receptor; Organism; Outcome; Pharmacology; Physiological; Play; Presynaptic Terminals; Process; Property; Proteins; Receptor Signaling; Resolution; Role; Schizophrenia; Signal Transduction; Structure; Susceptibility Gene; Synapses; Synaptic Transmission; Synaptic plasticity; System; Time; Transcript; Work; aging brain; alpha Bungarotoxin; base; experience; experimental study; flexibility; genetic analysis; genetic approach; genetic manipulation; imaging approach; innovation; kainate; mutant; nervous system disorder; neural circuit; neuropsychiatric disorder; neuropsychiatry; novel; postsynaptic; presynaptic; public health relevance; receptor; receptor function; relating to nervous system; response; screening; sensor; synaptic function; therapeutic target; trafficking

 DESCRIPTION (provided by applicant): Nervous systems from invertebrates to humans have shown remarkably resilient and adaptive abilities to maintain stable functionality despite challenges that may otherwise lead to suboptimal or uncontrolled activity. In each of these systems, perturbations to synaptic activity initially lead to corresponding alterations in synaptic strength. However, given sufficient time, nervous systems in these organisms adapt by modulating presynaptic release or postsynaptic neurotransmitter receptors to re-target previous levels of synaptic strength. This process, termed homeostatic synaptic plasticity, is thought to enable stable, yet flexible, synaptic activity and to play key roles in tuning neural function in health and disease. Yet there is a major gap in our knowledge of the molecular and cellular mechanisms that endow synapses with these extraordinary abilities. The long term goal of this proposal is to identify the genes and elucidate the mechanisms that achieve and maintain the homeostatic control of synaptic strength. To understand the principles governing homeostatic synaptic signaling, we will utilize the Drosophila neuromuscular junction, which has been established as a powerful genetic system to study this process. This proposal will use a combination of genetic analysis, electrophysiology, and imaging approaches to investigate the homeostatic mechanisms that enhance presynaptic release in response to a perturbation to postsynaptic neurotransmitter receptor function. In particular, three genes encoding neuronal transmembrane proteins have been identified that appear to function together in the presynaptic terminal to promote the calcium-dependent, homeostatic potentiation of synaptic transmission. Interestingly, these genes have been associated with epilepsy, schizophrenia, and bipolar disorder. The proposed experiments will first characterize these molecules in synaptic function and homeostatic plasticity. Confocal and super-resolution microscopy will then be utilized to reveal the subsynaptic localization and cellular activities of these proteins. Finally, complementary forward genetic screens are proposed to identify new genes that orchestrate homeostatic synaptic plasticity. Together, this work is expected to reveal new homeostatic genes and mechanisms that control the adaptive modulation of synaptic strength and provide a foundation from which to understand how transcellular homeostatic signaling systems more generally are established in the nervous system.

 描述（由适用提供）：从无脊椎动物到人类的神经系统表现出非常有弹性和适应性的能力，以维持稳定的功能，要求挑战，否则可能会导致次优或不受控制的活动。在每个系统中，合成活动的扰动最初导致突触的相应改变 力量。但是，在足够的时间内，这些生物体的神经系统通过调节突触前释放或突触后神经递质接收器来适应以前的突触强度的先前水平。这一过程称为体内稳态可塑性，被认为可以使稳定但灵活的合成活性促进，并在调整健康和疾病中的神经功能中起关键作用。然而，我们对分子和细胞机制的知识存在一个主要差距，这些机制具有这些非凡能力。该提案的长期目标是识别基因并阐明实现和维持突触强度的体内平衡控制的机制。为了理解管理稳态突触信号传导的原理，我们将利用果蝇神经肌肉连接，该连接已被确定为研究此过程的强大遗传系统。该建议将结合使用通用分析，电生理学和成像方法的组合来研究稳定的机制，从而响应于突触后神经递质受体功能而增强突触前释放。特别是，已经鉴定出了三个编码神经元跨膜蛋白的基因，它们似乎在突触前末端起作用，以促进突触传播的钙依赖性的，依赖性的稳态增强。患有癫痫，精神分裂症和躁郁症。提出的实验将首先在突触功能和稳态可塑性中表征这些分子。然后，将利用共焦和超分辨率显微镜揭示这些蛋白质的突触局部定位和细胞活性。最后，提出了完整的前向遗传筛选，以识别编排稳态合成可塑性的新基因。总之，这项工作有望揭示新的稳态基因和控制突触强度的适应性调节的机制，并为了解如何在神经系统中更普遍地建立了跨细胞稳态信号系统的基础。