Trans-synaptic control of presynaptic neurotransmitter release

突触前神经递质释放的跨突触控制

基本信息

批准号：
10157475
负责人：
Michael Mark Alexander Sutton
金额：
$ 43.18万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10157475
关键词：
Actin-Binding Protein Address Area Axon Biology Brain Brain-Derived Neurotrophic Factor Communication Complex Couples Coupling Cyclic AMP-Dependent Protein Kinases Cytoskeleton Data Defect Dendrites Development Disease Drosophila genus Electrophysiology (science)Elements Ensure Epilepsy FRAP1 gene Feedback Financial compensation Forms Controls Functional disorder Genetic Models Health Hippocampus (Brain)Homeostasis Human Hyperactivity Individual Intellectual functioning disability Investigation Laboratories Lead Link Maintenance Measurement Mediating Mediator of activation protein Memory Mendelian disorder Molecular Nature Nerve Block Neurodevelopmental Disorder Neurons Pathway interactions Peripheral Phosphorylation Play Post-Translational Protein Processing Presynaptic Terminals Process Proteasome Binding Proteomics Receptor Activation Regulation Role Signal Pathway Signal Transduction Site Synapses Synaptic Vesicles Synaptic plasticity Testing Translation Initiation Translations Work autism spectrum disorder base experimental study information processing insight mTORopathies multicatalytic endopeptidase complex nervous system disorder neuropsychiatric disorder neurotransmitter release novel optical imaging postsynaptic postsynaptic neurons presynaptic protein degradation recruit relating to nervous system ubiquitin-protein ligase voltage

项目摘要

Dysfunction in mechanisms that regulate the development, maintenance, and plasticity of synaptic connections have been linked to many neuropsychiatric and neurodevelopmental disorders, and thus a deep molecular understanding of these processes will be crucial in relieving the severe health burden these disorders impose. One aspect of synaptic communication that is critical for information processing in the brain is the maintenance of precise functional alignment between presynaptic neurotransmitter release and postsynaptic function at individual synapses, but the local signals that control this aspect of “synaptic homeostasis” are poorly understood. This project will focus on a recently discovered homeostatic pathway in hippocampal neurons that functions to tune presynaptic neurotransmitter release when postsynaptic receptor activation is deficient. My laboratory has recently described a unique homeostatic signaling pathway that couples synaptic inactivity to mTOR complex 1 (mTORC1) signaling in postsynaptic dendrites. mTORC1 activation, in turn, drives the local dendritic translation and release of brain-derived neurotrophic factor (BDNF), which elicits compensatory increases in neurotransmitter release from apposed presynaptic terminals but only if those terminals have been recently active. This state-dependent gating of synaptic homeostasis by local presynaptic activity ensures coupling of mTORC1 trans-synaptic signaling to spike-driven neurotransmitter release. During the previous period of support, we discovered that BDNF elicits presynaptic compensation via the proteasome-dependent degradation of the synaptic regulator tomosyn1 (Tomo1), which is catalyzed by the E3 ubiquitin ligase HRD1. During these investigations, we uncovered an unexpected and critical role for activity-dependent recruitment of the proteasome to axonal boutons. We now propose to test the central hypothesis that activity-dependent sequestration of proteasomes in presynaptic terminals confers state-dependent gating of synaptic homeostasis driven by postsynaptic mTORC1 signaling. Our investigations will examine how regulated phosphorylation of the 19S proteasome subunit Rpt6 dynamically regulates proteasome distribution in axons (Aim 1), define the core signaling pathway in axon terminals that links neural activity (and specifically, P/Q/N voltage-gated Ca2+ channel activity) with posttranslational modifications of the proteasome important for synaptic targeting (Aim 2), and define the molecular mechanisms that control proteasome sequestration in axon terminals (Aim 3). In each of these aims, the relationship of the mechanisms uncovered with mTORC1 trans-synaptic homeostatic signaling will be rigorously tested. The proposed experiments employ state of the art optical imaging of synaptic vesicle cycling and release, genetic models targeting mTORC1 signaling and proteasome phosphorylation, rigorous electrophysiological measurements, and are focused on a fundamentally new area of synaptic biology. The findings are expected to significantly advance our understanding of local homeostatic mechanisms that act to coordinate postsynaptic activity with spatial and temporal adjustments in presynaptic neurotransmitter release.

调节突触连接的发展，维护和可塑性的机制功能障碍已经与许多神经精神病学和神经发育障碍有关，因此对这些过程的深刻分子理解对于缓解这些疾病的严重健康爆发至关重要。突触通信对于大脑中信息处理至关重要的一个方面是维护在单个突触下突触前神经递质释放和突触后功能之间的精确功能对齐，但是控制“突触稳态”这一方面的局部信号知之甚少。该项目将重点介绍最近发现的海马神经元中的稳态途径，该途径起作用当突触后受体激活不足时，调节突触前神经递质释放。我的实验室最近，已经描述了一种独特的体内信号传导途径，该途径将突触不活跃与MTOR复合物1（MTORC1）在突触后树突中的信号传导。 MTORC1激活反过来驱动局部树突状脑衍生的神经营养因子（BDNF）的翻译和释放，这引起补偿性增加神经递质从应用的突触前终端释放积极的。局部突触前活动的这种依赖状态的突触体内平衡的门控能确保耦合 MTORC1反式突触信号传导，以尖峰驱动的神经递质释放。在上一个支持期间，我们发现BDNF通过蛋白酶体依赖性降解引起突触前补偿突触调节剂Tomosyn1（Tomo1），由E3泛素连接酶HRD1催化。在这些期间调查，我们发现了蛋白酶体对轴突胸子的活动依赖性募集的意外和关键作用。现在，我们建议检验中心假设，即突触前末端中蛋白酶体的活性依赖性隔离承认是由状态依赖性的突触稳态的门控，由突触后MTORC1信号传导。我们的调查将研究如何调节19S的磷酸化蛋白酶体亚基RPT6动态调节轴突中的蛋白酶体分布（AIM 1），定义了连接神经活动的轴突终端中的核心信号通路（特别是P/Q/N电压门控CA2+通道活动）具有对突触靶向重要的蛋白酶体的翻译后修饰（AIM 2），并且定义控制轴突末端中蛋白酶体固相的分子机制（AIM 3）。在每个这些目的，与MTORC1反式突触稳态信号传导发现的机制的关系将经过严格测试。提出的实验员工的最先进的突触囊泡的光学成像循环和释放，靶向MTORC1信号传导和蛋白酶体磷酸化的遗传模型，严格电生理测量，并集中在突触生物学的新领域。这期望发现将大大提高我们对当地稳态机制的理解在突触前神经递质释放中与空间和临时调整协调突触后活性。