Synaptic Control of Glutamate Homeostasis

谷氨酸稳态的突触控制

基本信息

批准号：
10362548
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10362548
关键词：
Aging Alzheimer&apos s Disease Autocrine Communication Autoreceptors Biological Biological Models Calcium Cells Cellular biology Chloride Channels Chlorides Chronic Couples Data Defect Development Disease Down-Regulation Drosophila genus Electrophysiology (science)Endocytosis Ensure Epilepsy Etiology Excitatory Synapse Fragile X Syndrome Functional Imaging Functional disorder Generations Genetic Glutamate Receptor Glutamate Transporter Glutamates Goals Growth Health Homeostasis Human Image Imaging Techniques Individual Invertebrates Knowledge Lead Mediating Mental Depression Modeling Molecular Nerve Degeneration Nervous system structure Neuroglia Neuromuscular Junction Neurons Organism Outcome Pharmacology Physiological Play Presynaptic Terminals Probability Process Property Regulation Reporting Research Rodent Role Schizophrenia Seizures Signal Transduction Site Stimulus Structure Synapses Synaptic Vesicles Synaptic plasticity System Technology Testing Therapeutic Toxic effect Work design excitotoxicity experience experimental study flexibility glutamate-gated chloride channel glutamatergic signaling in vivo innovation insight nervous system disorder neural circuit neuropathology neuropsychiatric disorder neurotransmission neurotransmitter release novel novel therapeutic intervention postsynaptic preservation presynaptic presynaptic neurons prevent receptor response reuptake synaptic function trafficking transmission process vesicular release

项目摘要

Homeostatic signaling systems are crucial forms of biological regulation that permit flexible yet stable information transfer in the nervous system. These fundamental mechanisms operate to maintain such properties as synaptic strength and glutamate levels within stable physiological ranges. Although intensive research has been focused on understanding how excitatory synapses are homeostatically modulated to stabilize synaptic strength, far less is known about how these synapses adjust to control glutamate release itself. Excess glutamate release can lead to a variety of diseases and dysfunctions in the nervous system, contributing to seizures, excitotoxity, and neurodegeneration. Here, we propose to characterize a glutamate homeostat that controls presynaptic function using the Drosophila neuromuscular junction as a unique and powerful model system. At this glutamatergic synapse, excess presynaptic glutamate secretion induces a homeostatic inhibition of neurotransmitter release, an adaptation referred to as presynaptic homeostatic depression (PHD). This process parallels a similar phenomenon observed in a variety of other organisms, including mammalian central synapses. We hypothesize that excess glutamate is sensed by a presynaptic glutamate receptor and activates an autocrine signaling system to homeostatically depress synaptic vesicle release. To test this model, we will use a systematic electrophysiology screen to test glutamate receptors in Drosophila for roles in PHD. Next, we will leverage a combination of cell biology, heterologous expression, pharmacology, and innovative functional imaging techniques to determine the mechanisms through which excess glutamate signals a precise reduction in presynaptic vesicle release. Finally, we will assess how synapses, neurons, and glia adapt to chronic glutamate imbalance using several approaches, including a cell-specific translational profiling technology we have developed as well as a new generation of glutamate indicators. Together, these experiments will advance our understanding of the mechanisms that endow synapses with the ability homeostatically tune glutamate release, and will identify maladaptive responses to glutamate imbalance in the nervous system. Ultimately, this knowledge will inform therapeutic strategies towards counteracting diseases associated with glutamate imbalance, including epilepsy, fragile X syndrome and neurodegeneration.

稳态信号系统是生物调节的重要形式，它允许灵活但神经系统中稳定的信息传递。这些基本机制的作用是将突触强度和谷氨酸水平等特性保持在稳定的生理范围内范围。尽管深入的研究一直集中在了解兴奋性突触如何被稳态调节以稳定突触强度，但人们对这些神经元如何发挥作用知之甚少。突触调节以控制谷氨酸本身的释放。过量的谷氨酸释放会导致多种神经系统疾病和功能障碍，导致癫痫发作、兴奋性中毒和神经变性。在这里，我们建议表征控制谷氨酸稳态使用果蝇神经肌肉接头作为独特而强大的模型来研究突触前功能系统。在这个谷氨酸突触，过量的突触前谷氨酸分泌会诱导神经递质释放的稳态抑制，一种称为突触前的适应稳态抑郁症（PHD）。这个过程与在一个实验中观察到的类似现象类似。各种其他生物体，包括哺乳动物中央突触。我们假设过量谷氨酸被突触前谷氨酸受体感知并激活自分泌信号系统稳态抑制突触小泡释放。为了测试这个模型，我们将使用系统电生理学筛查，测试果蝇谷氨酸受体在 PHD 中的作用。接下来，我们将结合细胞生物学、异源表达、药理学和创新的功能成像技术，以确定过量的机制谷氨酸发出突触前囊泡释放精确减少的信号。最后，我们将评估如何突触、神经元和神经胶质细胞使用多种方法适应慢性谷氨酸失衡，包括我们开发的细胞特异性翻译分析技术以及新的谷氨酸指示剂的产生。这些实验将共同推进我们的理解赋予突触稳态调节谷氨酸释放能力的机制，并将识别神经系统中谷氨酸失衡的适应不良反应。最终，这些知识将为对抗与以下疾病相关的疾病的治疗策略提供信息：谷氨酸失衡，包括癫痫、脆性 X 综合征和神经退行性疾病。