Latrophilin Function in Synapse Formation

Latrophilin 在突触形成中的功能

• 批准号: 10274019
• 负责人: Thomas C. Sudhof
• 金额: $ 73.07万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/10274019
• 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

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.

神经回路由突触构成，突触将神经元连接成巨大的网络。尽管许多神经回路已被表征，但构建其突触结构的分子和细胞机制仍然很大程度上未知。在建立神经回路突触结构的突触形成过程中，通过跨突触粘附分子的双向信号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通常容易导致神经精神疾病，这表明神经回路突触结构的功能障碍会导致神经精神疾病，尽管这些损伤的性质尚不清楚。我们的初步数据表明，在海马神经元中，兴奋性突触子集的形成需要 Latrophilins (Lphns)，这是一个由三个突触后粘附 GPCR 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，而且还参与确定其特异性。 Lphns 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，仍然未知。此外，人类 Lphn3 基因 (ADGRL3) 中的 SNP 会强力下调 Lphn3 的表达。本申请旨在检查介导Lphn依赖性突触形成的信号传导机制，探索Lphn如何确定突触特异性，并研究Lphn3表达的变化如何改变突触功能。具体来说，拟议的实验将测试总体假设：（1）Lphn 通过涉及局部限制信号传导的 GPCR 介导机制控制突触形成和维持，（2）不同的 Lphn 亚型​​通过其蛋白质相互作用和 GPCR 功能的序列特异性差异控制不同突触的形成，以及（3）Lphn3 表达的变化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的关键问题。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，范围从配体-受体复合物的生物物理学研究到细胞内信号传导的细胞生物学研究，再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 表达减少如何导致人类神经元突触变化。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的基础。