Latrophilin Function in Synapse Formation

Latrophilin 在突触形成中的功能

基本信息

批准号：
10434957
负责人：
Thomas C. Sudhof
金额：
$ 72.86万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10434957
关键词：
Address Adhesions Adhesives Affect Architecture Arrestins Behavior Binding Binding Sites Biological Biological Models Brain Brain region C-terminal Cell Adhesion Molecules Cells Cognition Cognitive Communication Complex Data Excitatory Synapse Family Functional disorder G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Genes Goals Hippocampus (Brain)Homo Human Impaired cognition Impairment Interneurons Investigation Life Ligand Binding Ligands Maintenance Mediating Molecular Mus Mutation Nature Neurons Pathogenesis Play Process Property Protein Isoforms Proteins Proteolysis Role Shapes Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Site Specific qualifier value Specificity Structure Synapses Synaptic Transmission Testing Ventral Striatum alpha-latrotoxin receptor behavioral study biophysical analysis cognitive change entorhinal cortex experimental study extracellular in vivo insight interdisciplinary approach interest neural circuit neuropsychiatric disorder postnatal postsynaptic receptor synaptic function synaptogenesis tool translational neuroscience

项目摘要

Neural circuits are constructed by synapses that connect neurons into vast networks. Although many neural circuits have been characterized, the molecular and cellular mechanisms that build their synaptic architecture remain largely unknown. During synapse formation that establishes the synaptic architecture of neural circuits, bi-directional signaling via trans-synaptic adhesion molecules is thought to control assembly of synapses. Strikingly, genetic changes in trans-synaptic adhesion molecules often predispose to neuropsychiatric disorders, suggesting that dysfunction of the synaptic architecture of neural circuits contributes to neuropsychiatric disorders, although the nature of these impairments is poorly understood. Our preliminary data show that in hippocampal neurons, formation of subsets of excitatory synapses requires latrophilins (Lphns), a family of three postsynaptic adhesion-GPCRs. Different Lphns mediate establishment of distinct synapses even in the same neuron, suggesting that they are involved not only in constructing synapses, but also in determining their specificity. How Lphns mediate synapse formation, and to what extent their synapse-formation function involves GPCR signaling or adhesive interactions, remains unknown. Moreover, SNPs in the human Lphn3 gene (ADGRL3) downregulate Lphn3 expression robustly. The present application proposes to examine the signaling mechanisms that mediate Lphn-dependent synapse formation, to explore how Lphns determine synapse specificity, and to investigate how changes in Lphn3 expression change synaptic function. Specifically, the proposed experiments will test the overall hypotheses that (1) Lphns control synapse formation and maintenance by a GPCR-mediated mechanism involving locally restricted signaling, that (2) different Lphn isoforms control formation of distinct synapses via sequence-specific differences in their protein interactions and GPCR function, and that (3) changes in Lphn3 expression impair formation of a specific subset of synapses. Three Specific Aims will test these hypotheses, thus targeting key questions that are most relevant for understanding how neural circuits are wired and how impairment of neural circuits alter cognition. Using both mouse and human neurons as a model system, the project will pursue broadly interdisciplinary approaches in both mice and human neurons that range from biophysical studies of ligand-receptor complexes to cell-biological investigations of intracellular signaling to behavioral studies probing for cognitive changes. Thereby, this application will provide insight into how Lphns drive synapse formation in mice, and how decreased expression of Lphn3 predisposes to synaptic changes in human neurons. Addressing these questions is of paramount interest in basic and translational neuroscience because neural circuits that process the brain’s information are constructed by synapse formation, and dysfunction or imbalance of synaptic communication in neural circuits likely underlies the pathogenesis of neuropsychiatric disorders.

神经回路是由将神经元连接成巨大网络的突触构建的，尽管许多神经回路已经被表征，但在建立神经回路突触结构的突触形成过程中，构建其突触结构的分子和细胞机制仍然很大程度上未知。通过跨突触粘附分子的信号传导被认为可以控制突触的组装，引人注目的是，跨突触粘附分子的遗传变化往往容易导致神经精神疾病。神经回路突触结构的功能障碍会导致神经精神疾病，尽管我们对这些损伤的性质知之甚少，但我们的初步数据表明，在海马神经元中，兴奋性突触亚群的形成需要懒惰蛋白（Lphns），这是一个由三个突触后蛋白组成的家族。即使在同一神经元中，不同的 Lphns 也会介导不同突触的建立，这表明它们不仅参与突触的构建，此外，Lphn 如何介导突触形成，以及它们的突触形成功能在多大程度上涉及 GPCR 信号传导或粘附相互作用，目前仍不清楚。该申请旨在检查介导 Lphn 依赖性突触形成的信号机制，探索 Lphn 如何确定突触特异性，并研究 Lphn3 的变化如何具体来说，所提出的实验将测试以下总体假设：(1) Lphn 涉及通过 GPCR 介导的局部信号传导机制控制突触形成和维持，(2) 不同的 Lphn 亚型通过序列控制限制性突触的形成 -它们的蛋白质相互作用和 GPCR 功能的具体差异，以及 (3) Lphn3 表达的变化会损害特定突触子集的形成，三个具体目标将测试这些假设，从而针对以下关键问题。与理解神经回路如何连接以及神经回路损伤如何改变认知最相关，该项目将使用小鼠和人类神经元作为模型系统，在小鼠和人类神经元中寻求广泛的跨学科方法，范围包括配体的生物物理学研究。受体复合物到细胞内信号传导的细胞生物学研究，到探索认知变化的行为研究，因此，该应用将深入了解 Lphn 如何驱动小鼠突触形成，以及 Lphn3 表达减少如何导致突触发生。解决这些问题对于基础神经科学和转化神经科学至关重要，因为处理大脑信息的神经回路是通过突触形成构建的，神经回路中突触通讯的功能障碍或不平衡可能是神经精神疾病的发病机制。