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Synaptic Control of Glutamate Homeostasis

谷氨酸稳态的突触控制

基本信息

批准号：
9888456
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/9888456
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.

动态平衡信号系统是生物调节的重要形式，允许灵活而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维持在稳定的生理水平范围。尽管密集的研究一直集中在了解兴奋性突触如何是通过稳态调节来稳定突触强度的，但关于它们是如何发挥作用的知之甚少。突触进行调节以控制谷氨酸自身的释放。过多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、兴奋性毒性和神经退行性变。在这里，我们建议描述一种控制谷氨酸稳态的利用果蝇神经肌肉接头作为一种独特而强大的模型的突触前功能系统。在这个谷氨酸能突触，过量的突触前谷氨酸分泌诱导了神经递质释放的动态平衡抑制，一种称为突触前的适应动态平衡抑制(PHD)。这一过程与在多种其他生物，包括哺乳动物的中央突触。我们假设过多的谷氨酸由突触前谷氨酸受体感受，并激活自分泌信号体内恒定抑制突触囊泡释放的系统。为了测试此模型，我们将使用系统电生理学筛选以测试果蝇谷氨酸受体在PHD中的作用。接下来，我们将利用细胞生物学、异源表达、药理学和创新的功能成像技术，以确定过度谷氨酸是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通过几种途径适应慢性谷氨酸失衡，包括我们开发的特定于细胞的翻译图谱技术以及新的谷氨酸指示剂的生成。总而言之，这些实验将增进我们对在赋予突触自我平衡调节谷氨酸释放能力的机制中，并将确定神经系统中对谷氨酸失衡的适应不良反应。最终，这一知识将成为对抗与以下疾病相关疾病的治疗策略的依据谷氨酸失衡，包括癫痫、脆性X综合征和神经变性。