Molecular Mechanisms Governing the Homeostatic Control of Synaptic Strength

突触强度稳态控制的分子机制

基本信息

批准号：
9412197
负责人：
DION KAI DICKMAN
金额：
$ 46.75万
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 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9412197
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

项目摘要

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（由申请人提供）：从无脊椎动物到人类的神经系统都表现出弹性和适应能力，尽管存在可能导致次优或不受控制的活动的挑战，但在这些系统中，对突触活动的扰动最初会导致相应的改变。在突触中然而，如果有足够的时间，这些生物体中的神经系统会通过调节突触前释放或突触后神经递质受体来重新定位以前的突触强度水平，这一过程被称为稳态突触可塑性，被认为可以实现稳定而灵活的突触。然而，从长远来看，我们对赋予突触这些非凡能力的分子和细胞机制的了解还存在重大差距。该提案的目标是识别基因并阐明实现和维持突触强度稳态控制的机制。为了了解控制稳态突触信号传导的原理，我们将利用果蝇神经肌肉接头，它已被确立为强大的遗传系统。该提案将结合遗传分析、电生理学和成像方法来研究增强突触前释放以应对突触后扰动的稳态机制。特别是，已鉴定出编码神经元跨膜蛋白的三个基因，它们似乎在突触前末端一起发挥作用，以促进突触传递和双相情感障碍的钙依赖性稳态增强。然后将利用共焦和超分辨率显微镜来揭示突触功能和稳态可塑性。最后，提出了互补的前向遗传筛选来识别协调稳态突触可塑性的新基因，这项工作有望揭示控制突触强度和适应性调节的新稳态基因和机制。为理解神经系统中更普遍的跨细胞稳态信号系统如何建立提供了基础。