CRCNS US-German Research Proposal: Quantitative and Computational Dissection of Glutamatergic Crosstalk at Tripartite Synapses

CRCNS 美德研究提案：三方突触谷氨酸能串扰的定量和计算剖析

基本信息

批准号：
10612169
负责人：
Ghanim Ullah
金额：
$ 12.58万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612169
关键词：
Affect Astrocytes Bioenergetics Brain Brain region Cell physiology Cells Cellular Morphology Chemical Synapse Communication Computer Models Data Development Disease Dissection Electrophysiology (science)Event Excitatory Synapse Extracellular Space Feedback Florida Fluorescence Microscopy Future German population Germany Giant Cells Glutamate Transporter Glutamates Heterogeneity Hippocampus Homeostasis Impairment Individual Ion Transport Ischemic Stroke Link Measures Modeling Molecular Monitor Morphology Mus N-Methyl-D-Aspartate Receptors Neocortex Neuronal Plasticity Neurons Pathway interactions Pharmacology Play Preparation Process Production Property Protons Research Research Proposals Role Side Signal Transduction Site Specificity Structure Synapses Synaptic Cleft Synaptic Transmission Techniques Testing Time Tissues Universities Viral Work density design driving force excitotoxicity experimental study extracellular fluorescence imaging fluorescence lifetime imaging image processing insight multi-scale modeling multiphoton imaging neocortical nervous system disorder neuronal cell body neuronal excitability neurotransmission novel novel strategies pharmacologic postsynaptic predictive modeling presynaptic spatiotemporal stoichiometry synaptic function tool transmission process uptake

项目摘要

CRCNS US-German Research Proposal: Quantitative and computational dissection of glutamatergic crosstalk at tripartite synapses (1) Christine R Rose, Heinrich Heine University, Düsseldorf, Germany (2) Christian Henneberger, University of Bonn, Germany (3) Ghanim Ullah, University of South Florida, Tampa, FL, USA Project Description 1 Introduction and Background Transmission at chemical synapses is the central mechanism by which information is transferred between neurons. Synaptic connections such as glutamatergic excitatory synapses are often perceived and modeled as point-to-point connections. However, there is substantial evidence that crosstalk between various glutamatergic synapses can occur when the presynaptically released glutamate is sensed not only by its direct postsynaptic partner but also by nearby synapses of the same and other neurons [4]. Notably, this phenomenon termed “glutamate spillover” not only defines the input-specificity of a given synaptic connection and its crosstalk to neighboring synapses, but is also involved in and controlled by activity-dependent plasticity [1, 7, 8]. How easily glutamate escapes from its release site and how far it spreads into the tissue depends on the morphological and molecular properties of the extracellular space (ECS) as well as on the efficacy of glutamate clearance, which primarily depends on astrocytic uptake [11, 12]. We and others have shown that the efficacy of perisynaptic glutamate uptake by astrocytes displays a remarkable heterogeneity between brain regions and, importantly, can vary drastically from one synapse to the next within a brain region [3, 7, 8]. This is in part because the morphological coverage of synapses by perisynaptic astrocyte processes (PAPs) can differ strongly between individual synapses [14]. Moreover, the Henneberger lab has recently shown that higher synaptic coverage by PAPs correlates with a higher local efficacy of glutamate uptake [3]. We have also demonstrated that in addition to being heterogeneous, astrocytic glutamate uptake and PAPs morphology both are controlled by neuronal plasticity [1]. Moreover, glutamate uptake is governed by the transporters’ stoichiometry, importing one glutamate molecule into the astrocyte by using the energy gained from co-transporting three Na+ and one proton down the electrochemical gradients, whilst also exporting one K+ [12]. While the inwardly-directed Na+ gradient is the main driving force for glutamate uptake, recent work by Rose lab and others have shown that glutamatergic activity causes local or global Na+ transients in astrocytes ([Na+]A) [15]. In the mouse hippocampus, astrocytic Na+ signals in fact arise predominately due to the activity of glutamate transporters themselves, degrading the Na+ gradient and thereby transiently weakening uptake capacity in a negative feedback-loop [15-17]. In the neocortex, glutamatergic synaptic activity in addition results in prominent Na+ influx through NMDA receptors, boosting astrocyte Na+ gradients [18]. Thus, it is increasingly appreciated that astrocytic glutamate uptake is neither static nor uniform. First, it is functionally dependent on the gradients of the transported ions which dynamically change with synaptic transmission [12]. Second, it is plastic because structural remodeling of PAPs on time scales of minutes profoundly alters perisynaptic glutamate spread [1]. Therefore, the emerging hypothesis is that the degree of glutamate spillover and, therefore, synaptic crosstalk in most brain regions are dynamically regulated and controlled at the level of the astrocytes. Furthermore, since a single astrocyte can contact thousands of synapses of various neurons, it has the potential to locally control the crosstalk of many synapses. In such a scenario, an astrocyte, or a subcellular domain of it, can coordinate crosstalk between many glutamatergic synapses on different neurons. Thereby, astrocytes and their PAPs set the spatial fidelity of glutamatergic synaptic transmission and as a consequence profoundly control neuronal signal exchange. So far, these important hypotheses remain largely untested. We will fill this gap by combining quantitative fluorescence imaging, astrocytic manipulations, and predictive computer modelling. This will be accomplished by investigating perisynaptic astrocytic Na+ gradients, the main driving force of glutamate uptake, and local mechanisms controlling them 1

CRCNS 美德研究提案：定量和计算剖析三方突触的谷氨酸能串扰 (1) Christine R Rose，海因里希海涅大学，杜塞尔多夫，德国 (2) Christian Henneberger，德国波恩大学 (3) Ghanim Ullah，南佛罗里达大学，美国佛罗里达州坦帕项目描述 1 简介和背景化学突触的传递是信息传递的核心机制神经元之间转移的连接，例如谷氨酸兴奋性。突触通常被视为点对点连接并建模为点对点连接。大量证据表明，当突触前释放的谷氨酸不仅被其直接的突触后伙伴感知值得注意的是，这种现象也受到相同神经元和其他神经元附近突触的影响。术语“谷氨酸溢出”不仅定义了给定突触的输入特异性连接及其与邻近突触的串扰，但也参与并受其控制活动依赖性可塑性 [1,7,8]。谷氨酸从其释放位点逃逸的容易程度以及它扩散到组织中的距离取决于细胞外空间 (ECS) 的形态和分子特性：以及谷氨酸清除的功效，这主要取决于星形胶质细胞的摄取 [11, 12] 我们和其他人已经证明突触周围谷氨酸摄取的功效。星形胶质细胞在大脑区域之间表现出显着的异质性，重要的是，可以大脑区域内的一个突触与下一个突触之间存在显着差异 [3,7,8]。因为突触的形态被突触周围星形胶质细胞突起（PAP）覆盖各个突触之间可能存在很大差异[14]。最近表明，PAP 较高的突触覆盖率与较高的局部功效相关我们还证明，除了异质性之外，星形胶质细胞谷氨酸摄取和 PAP 形态均受神经元可塑性控制 [1] 此外，谷氨酸的吸收受转运蛋白的化学计量控制，导入一个。利用共同运输三者所获得的能量将谷氨酸分子转移到星形胶质细胞中 Na+ 和一个质子沿着电化学梯度下降，同时还输出一个 K+ [12]。虽然向内的 Na+ 梯度是谷氨酸吸收的主要驱动力，但最近 Rose 实验室和其他人的工作表明，谷氨酸活性会导致局部或整体 Na+ 星形胶质细胞中的瞬变 ([Na+]A) [15] 实际上，在小鼠海马中，星形胶质细胞发出 Na+ 信号。主要是由于谷氨酸转运蛋白本身的活性，降解了 Na+ 梯度，从而暂时削弱负反馈回路中的吸收能力 [15-17] 在新皮质中，谷氨酸能突触活动另外导致显着的Na+。通过 NMDA 受体流入，提高星形胶质细胞 Na+ 梯度 [18]。因此，人们越来越认识到星形胶质细胞的谷氨酸摄取既不是静态的也不是静态的。首先，它在功能上取决于传输离子的梯度。随着突触传递而动态变化[12]，其次，它是可塑的，因为结构。 PAP 在分钟时间尺度上的重塑深刻地改变了突触周围谷氨酸的扩散 [1] 因此，新出现的假设是谷氨酸溢出的程度，因此，大多数大脑区域的突触串扰是动态调节和控制的此外，由于单个星形胶质细胞可以接触数千个。各种神经元的突触，它有潜力局部控制许多神经元的串扰在这种情况下，星形胶质细胞或其亚细胞域可以协调。不同神经元上的许多谷氨酸突触之间的串扰，从而形成星形胶质细胞。他们的 PAP 设定了谷氨酸能突触传递的空间保真度，并作为后果深刻地控制着神经信号交换。到目前为止，这些重要的假设在很大程度上尚未得到检验，我们将通过以下方式填补这一空白。结合定量荧光成像、星形胶质细胞操作和预测这将通过研究突触周围星形细胞 Na+ 来完成。梯度，谷氨酸吸收的主要驱动力，以及控制它们的局部机制 1