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病理学相关，例如大脑功能的阿尔茨海默氏病由于线粒体呼吸缺陷和细胞能量丧失而受到损害。该项目的长期目标是为了改善因线粒体功能障碍而导致的神经传递缺陷，以阻止疾病发展为后来的退化阶段，增加了越来越多的人群中的健康状态相关的神经疾病。突触功能的生物能源的基本机制正常组织必须首先解决，以治愈这些疾病。我们在这个项目中的目标是两个方面。首先，线粒体Ca2+摄取量ATP的产生响应于活动的程度。其次，在突触前终端使用补偿性策略以延迟能量损失的程度将当线粒体功能受损时，请确定。该项目的结果将提供明确的机械深入了解突触线粒体的CA2+延伸和产生ATP的作用，这是必不可少的第一步目前不清楚。 PI开发了几种新颖的方法，使我们能够剖析过去的生物能策略使用电生理学，Ca2+成像和 ATP成像。与小型传统突触相反，啮齿动物中的巨型“类似花萼”令人兴奋的突触听觉脑干允许从突触前终端进行直接的全细胞记录。这个实验可访问性允许操纵突触前[Ca2+]和[ATP]，因此可以剖析突触线粒体的相互依存的Ca2+延伸和能量支撑作用。在第一个特定目标中线粒体钙能形成蛋白（MCU）有助于线粒体呼吸和ATP稳态的程度将确定以下突触活动。第二个特定目标将剖析线粒体Ca2+摄取与已制备的突触传播和突触前的呼吸可塑性。也就是说，MCU对于突触时的Ca2+缓冲或ATP稳态更重要吗？具体目标三，糖酵解和线粒体呼吸之间的代谢切换的结果将在正常突触中检查传输受损。该项目将详细了解由突触以支持物理和病理环境中的合成传播。这些知识将确定可行的干预途径，用于恢复可以利用能量的突触的功能治疗以减轻与疾病相关的突触功能障碍。