Activity-dependent energy homeostasis at the presynaptic terminal

突触前末梢活动依赖性能量稳态

基本信息

批准号：
10394964
负责人：
ROBERT B RENDEN
金额：
$ 53.91万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394964
关键词：
ATP Synthesis Pathway Acute Address Affect Aging Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease brain Architecture Auditory Bioenergetics Biological Assay Brain Brain Stem Buffers Cells Cellular Stress Chronic Creatine Kinase Defect Disease Disease Progression Electric Stimulation Electrophysiology (science)Energy Supply Excitatory Synapse Frequencies Functional Imaging Functional disorder Generations Glycolysis Goals Homeostasis Huntington Disease Image Impairment Intervention Knowledge Measures Mediating Metabolic Mitochondria Monitor Motivation Mus Natural regeneration Neurodegenerative Disorders Neurons Normal tissue morphology Outcome Parkinson Disease Pathologic Pathology Pathway interactions Phase Physiological Population Positioning Attribute Preparation Presynaptic Terminals Production Recycling Research Resolution Respiration Rodent Role Route Shapes Synapses Synaptic Transmission Synaptic plasticity System Techniques Testing Therapeutic Time Tissues Whole-Cell Recordings Work age related base calcium uniporter functional restoration healthspan imaging probe insight mitochondrial dysfunction nervous system disorder neuron loss neurotransmission normal aging novel strategies presynaptic repaired response synaptic function transmission process uptake

项目摘要

This work is relevant to both normal aging and pathologies like Alzheimer’s disease, where brain function is impaired due to defective mitochondrial respiration and loss of cellular energy. The long-term goal of this project is to ameliorate neurotransmission defects due to mitochondrial dysfunction, as a way to stop disease progression to later degenerative stages, increasing healthspan in populations increasingly subject to age- related neurological diseases. Fundamental mechanisms underlying the bioenergetics of synaptic function in normal tissue must be resolved first, to cure these diseases. Our goals in this project are two-fold. First, the extent to which mitochondrial Ca2+ uptake facilitates ATP production in response to activity will be defined. Second, the extent that compensatory strategies are utilized at the presynaptic terminal to delay energy loss will be determined when mitochondrial function is impaired. Results from this project will provide clear mechanistic insight into the Ca2+-buffering and ATP-producing roles of synaptic mitochondria, an essential first step that is currently unclear. The PI has developed several novel approaches that allow us to dissect the bioenergetic strategies used to support transmission at the mouse calyx of Held, using a combination of electrophysiology, Ca2+ imaging, and ATP imaging. In contrast to small conventional synapses, giant ‘calyx-like’ excitatory synapses in the rodent auditory brainstem allow direct whole-cell recordings from the presynaptic terminal. This experimental accessibility permits manipulation of presynaptic [Ca2+] and [ATP], making it possible to dissect the interdependent Ca2+-buffering and energy-supporting roles of synaptic mitochondria. In the first Specific Aim, the extent that the mitochondrial calcium uniporter (MCU) facilitates mitochondrial respiration and ATP homeostasis following synaptic activity will be determined. The second Specific Aim will dissect the importance of mitochondrial Ca2+ uptake versus facilitated respiration on synaptic transmission and presynaptic short-term plasticity. Namely, is the MCU more important for Ca2+ buffering or ATP homeostasis at the synapse? In Specific Aim three, the consequence of metabolic switching between glycolysis and mitochondrial respiration in support of transmission will be examined in normal synapses, and in cases where MCU function is acutely or chronically impaired. This project will provide a detailed understanding of the range of metabolic strategies that are employed by synapses to support synaptic transmission in physiological and pathological settings. This knowledge will identify viable routes of intervention for restoring function to energy-deficient synapses that can be leveraged therapeutically to alleviate disease-related synaptic dysfunction.

这项工作与正常衰老和阿尔茨海默氏病等病理学相关，阿尔茨海默氏病是大脑功能受损的疾病。由于线粒体呼吸缺陷和细胞能量损失而受损该项目的长期目标。是为了改善由于线粒体功能障碍引起的神经传递缺陷，作为阻止疾病的一种方法进展到后期退行性阶段，增加了越来越受年龄影响的人群的健康寿命相关神经系统疾病的基本机制。要治愈这些疾病，必须首先解决正常组织问题。将定义线粒体 Ca2+ 吸收在多大程度上促进响应活动的 ATP 产生。其次，在突触前末端利用补偿策略来延迟能量损失的程度将当线粒体功能受损时，该项目的结果将提供清晰的机制。深入了解突触线粒体的 Ca2+ 缓冲和 ATP 生成作用，这是重要的第一步目前还不清楚。 PI 开发了几种新颖的方法，使我们能够剖析用于结合电生理学、Ca2+ 成像和 ATP 成像与小型传统突触不同，啮齿类动物具有巨大的“花萼状”兴奋性突触。听觉脑干允许从突触前终端直接进行全细胞记录。可及性允许操纵突触前 [Ca2+] 和 [ATP]，从而可以解剖突触线粒体相互依赖的 Ca2+ 缓冲和能量支持作用。线粒体钙单向转运蛋白 (MCU) 促进线粒体呼吸和 ATP 稳态的程度将确定以下突触活动。第二个具体目标将剖析其重要性。线粒体 Ca2+ 摄取与突触传递和突触前短期的促进呼吸即，MCU 对于突触处的 Ca2+ 缓冲或 ATP 稳态更重要吗？目标三，支持糖酵解和线粒体呼吸之间代谢转换的结果将在正常突触中检查传输的情况，并且在 MCU 功能急性或慢性的情况下受损。该项目将提供对所采用的代谢策略范围的详细了解这些知识将识别突触在生理和病理环境中支持突触传递。恢复可利用的能量缺乏突触功能的可行干预途径治疗缓解疾病相关的突触功能障碍。