The multiple roles of mitochondria in synaptic transmission

线粒体在突触传递中的多重作用

基本信息

批准号：
7583528
负责人：
GREGORY TALISKER MACLEOD
金额：
$ 24.85万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-29 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7583528
关键词：
Accounting Action Potentials Address Architecture Area Brain Buffers Cell membrane Cells Chemosensitization Chromosome Pairing Communication Condition Cytosol Data Desire for food Drosophila genus Endoplasmic Reticulum Fire - disasters Foundations Generations Genes Genetic Glare Goals Human body Image Imaging Techniques Influentials Knowledge Learning Life Link Measurement Measures Memory Mitochondria Modeling Monitor Movement Mutation Nature Nerve Nerve Degeneration Nerve Endings Nervous System Physiology Neurons Numbers Organelles Pathogenesis Pattern Peripheral Phase Production Protons Public Health Range Reactive Oxygen Species Recording of previous events Reporting Research Residual state Role Site Source Synapses Synaptic Transmission Synaptic plasticity Techniques Testing Thinking Time Training gene therapy in vivo mitochondrial dysfunction nervous system disorder neurotransmission neurotransmitter release novel response uptake voltage

项目摘要

DESCRIPTION (provided by applicant): Our overall goal is to determine the mitochondrial mechanisms that influence neurotransmitter release and the impact of these mechanisms across different synapse types. Mitochondria in nerve terminals are well placed to influence neurotransmitter release but their means of influence have resisted clarification. Many facets of mitochondrial function have been directly implicated in synaptic plasticity but due to the interwoven nature of these activities (ATP production; Ca2+ and Na+ handling; extrusion of protons; release of reactive oxygen species) it has been difficult to identify those that make the primary impact. A second area that requires clarification is the role of mitochondria in different forms of short-term synaptic plasticity. Although mitochondria have an established role in the post-tetanic potentiation of synaptic strength, little is known about their impact on other forms of short-term synaptic plasticity. Lastly, while we know that mitochondria influence neurotransmitter release and synaptic plasticity in large nerve terminals very little is known about their influence in small terminals, typical of the mammalian CNS. These are glaring gaps in our knowledge, particularly as synaptic plasticity allows for changes in synaptic strength, a phenomenon underlying learning and memory. More troubling perhaps, is that mitochondrial dysfunction is found at the epicenter of many neurodegenerative conditions for which the pathogenesis and progression are poorly understood. The central hypothesis is that mitochondria influence neurotransmitter release through multiple mechanisms, and the architecture of the nerve terminal and its firing history determines which mechanism is influential. We bring a combined electrophysiological, imaging and genetic approach to address this hypothesis at Drosophila nerve terminals in vivo, and we introduce a novel peripheral synapse with a single release-site as a model for central synapses with the same architecture. We will test the ability of mitochondrial Ca2+ uptake to limit the amplitude of Ca2+ transients and neurotransmitter release during short trains of action potentials - a firing pattern common in central neurons (Aim 1). Emphasis will be placed on single release-site nerve terminals where we observe mitochondria to have a voracious appetite for Ca2+. We will determine if mitochondria in these terminals are more effective at taking up Ca2+ because they are able to take up Ca2+ directly from Ca2+ microdomains (Aim 2). We will determine whether mitochondrial ATP production, rather than Ca2+ uptake, is the principle mechanism that maintains synchronous release during sustained nerve firing (Aim 3). Finally we will test the requirement for mitochondrial Ca2+ release in the post-tetanic potentiation of transmitter release, and examine the transfer of Ca2+ between mitochondria and the endoplasmic reticulum (Aim 4). An understanding of how mitochondrial function influences synaptic transmission under non-pathological conditions will provide the foundation required to understand the role of mitochondria in pathological conditions. PUBLIC HEALTH RELEVANCE: Mitochondria are organelles within all cells of the human body that generate most of our energy. They concentrate within nerve endings where they power communication between nerves, a fundamental activity of the brain. However, little is known about the way in which they contribute to the function of the nervous system and this is troubling, as mitochondrial malfunction is implicated in many diseases of the nervous system. We are currently examining how mitochondria influence the communication between healthy nerves so that we may understand the ways in which they may become involved in neurodegenerative conditions.

描述（由申请人提供）：我们的总体目标是确定影响神经递质释放的线粒体机制以及这些机制对不同突触类型的影响。神经末梢中的线粒体能够很好地影响神经递质的释放，但其影响方式尚未得到澄清。线粒体功能的许多方面都与突触可塑性直接相关，但由于这些活动的交织性质（ATP 产生；Ca2+ 和 Na+ 处理；质子的挤出；活性氧的释放），因此很难识别那些使突触可塑性发挥作用的因素。主要影响。第二个需要澄清的领域是线粒体在不同形式的短期突触可塑性中的作用。尽管线粒体在强直后突触强度增强中具有确定的作用，但人们对其对其他形式的短期突触可塑性的影响知之甚少。最后，虽然我们知道线粒体影响大神经末梢的神经递质释放和突触可塑性，但我们对它们对哺乳动物中枢神经系统典型的小神经末梢的影响知之甚少。这些是我们知识中的明显差距，特别是突触可塑性允许突触强度的变化，这是学习和记忆的基础现象。也许更令人不安的是，线粒体功能障碍是许多神经退行性疾病的核心，而人们对其发病机制和进展知之甚少。核心假设是线粒体通过多种机制影响神经递质释放，神经末梢的结构及其放电历史决定了哪种机制具有影响力。我们采用电生理学、成像和遗传学相结合的方法来解决果蝇体内神经末梢的这一假设，并引入一种具有单一释放位点的新型外周突触作为具有相同结构的中央突触的模型。我们将测试线粒体 Ca2+ 摄取限制 Ca2+ 瞬变幅度和短动作电位序列（中枢神经元常见的放电模式）期间神经递质释放的能力（目标 1）。重点将放在单个释放位点神经末梢上，我们观察到线粒体对 Ca2+ 有贪婪的胃口。我们将确定这些末端的线粒体是否能够更有效地吸收 Ca2+，因为它们能够直接从 Ca2+ 微域吸收 Ca2+（目标 2）。我们将确定线粒体 ATP 的产生（而不是 Ca2+ 的吸收）是否是在持续神经放电期间维持同步释放的主要机制（目标 3）。最后，我们将测试强直后递质释放增强对线粒体 Ca2+ 释放的需求，并检查线粒体和内质网之间 Ca2+ 的转移（目标 4）。了解线粒体功能如何影响非病理条件下的突触传递将为理解线粒体在病理条件下的作用提供所需的基础。公共卫生相关性：线粒体是人体所有细胞内的细胞器，产生我们的大部分能量。它们集中在神经末梢内，为神经之间的交流提供动力，这是大脑的基本活动。然而，人们对它们对神经系统功能的贡献方式知之甚少，这令人不安，因为线粒体功能障碍与许多神经系统疾病有关。我们目前正在研究线粒体如何影响健康神经之间的通讯，以便我们了解它们可能参与神经退行性疾病的方式。