Latrophilin Function in Synapse Formation
Latrophilin Function in Synapse Formation
批准号:
10434957
负责人:
Thomas C. Sudhof
金额:
$72.86万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-07-01 至 2026-04-30
关键词:
AddressAdhesionsAdhesivesAffectArchitectureArrestinsBehaviorBindingBinding SitesBiologicalBiological ModelsBrainBrain regionC-terminalCell Adhesion MoleculesCellsCognitionCognitiveCommunicationComplexDataExcitatory SynapseFamilyFunctional disorderG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGTP-Binding ProteinsGenesGoalsHippocampus (Brain)HomoHumanImpaired cognitionImpairmentInterneuronsInvestigationLifeLigand BindingLigandsMaintenanceMediatingMolecularMusMutationNatureNeuronsPathogenesisPlayProcessPropertyProtein IsoformsProteinsProteolysisRoleShapesSignal PathwaySignal TransductionSignaling MoleculeSignaling ProteinSiteSpecific qualifier valueSpecificityStructureSynapsesSynaptic TransmissionTestingVentral Striatumalpha-latrotoxin receptorbehavioral studybiophysical analysiscognitive changeentorhinal cortexexperimental studyextracellularin vivoinsightinterdisciplinary approachinterestneural circuitneuropsychiatric disorderpostnatalpostsynapticreceptorsynaptic functionsynaptogenesistooltranslational neuroscience
中文摘要
神经回路是由突触构成的,突触将神经元连接成庞大的网络。尽管许多神经回路已被描述,但构建其突触结构的分子和细胞机制在很大程度上仍是未知的。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有助于神经精神疾病,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,兴奋性突触亚群的形成需要嗜latrophilins (Lphns),这是一个由三种突触后粘附- gpcr组成的家族。即使在同一个神经元中,不同的lphn也介导不同突触的建立,这表明它们不仅参与突触的构建,而且还决定了突触的特异性。lphn是如何介导突触形成的,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,目前尚不清楚。此外,人类Lphn3基因(ADGRL3)中的snp显著下调Lphn3的表达。本申请旨在研究介导lphn依赖性突触形成的信号机制,探索lphn如何决定突触特异性,并研究Lphn3表达的变化如何改变突触功能。具体来说,这些实验将验证以下假设:(1)Lphn通过GPCR介导的机制控制突触的形成和维持,涉及局部限制性信号传导;(2)不同的Lphn同种异构体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;(3)Lphn3表达的变化损害特定突触子集的形成。Three Specific Aims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。使用小鼠和人类神经元作为模型系统,该项目将在小鼠和人类神经元中进行广泛的跨学科研究,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Lphns如何驱动小鼠突触形成,以及Lphn3表达降低如何导致人类神经元突触变化。解决这些问题对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由突触形成构建的,神经回路中突触通信的功能障碍或不平衡可能是神经精神疾病发病机制的基础。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Latrophilin Function in Synapse Formation
-
批准号:10611452
-
项目类别:
-
资助金额:$68.47万
-
财政年份:2021
-
负责人:Thomas C. Sudhof
-
依托单位:
Regulation of cholesterol by y-secretase and ApoE: Implications for AD pathogenesis and synaptic function
-
批准号:10601030
-
项目类别:
-
资助金额:$76.3万
-
财政年份:2021
-
负责人:Thomas C. Sudhof
-
依托单位:
Regulation of cholesterol by y-secretase and ApoE: Implications for AD pathogenesis and synaptic function
-
批准号:10379401
-
项目类别:
-
资助金额:$76.3万
-
财政年份:2021
-
负责人:Thomas C. Sudhof
-
依托单位:
Latrophilin Function in Synapse Formation
-
批准号:10274019
-
项目类别:
-
资助金额:$73.07万
-
财政年份:2021
-
负责人:Thomas C. Sudhof
-
依托单位:
The role of Myt1l in the developing and adult mouse brain
-
批准号:9904331
-
项目类别:
-
资助金额:$73.49万
-
财政年份:2019
-
负责人:Thomas C. Sudhof
-
依托单位:
The role of Myt1l in the developing and adult mouse brain
-
批准号:10579921
-
项目类别:
-
资助金额:$69.82万
-
财政年份:2019
-
负责人:Thomas C. Sudhof
-
依托单位:
The role of Myt1l in the developing and adult mouse brain
-
批准号:10333320
-
项目类别:
-
资助金额:$69.82万
-
财政年份:2019
-
负责人:Thomas C. Sudhof
-
依托单位:
Function of Neurexins
-
批准号:8932978
-
项目类别:
-
资助金额:$71.63万
-
财政年份:2015
-
负责人:Thomas C. Sudhof
-
依托单位:
Function of Neurexins
-
批准号:9033151
-
项目类别:
-
资助金额:$73.15万
-
财政年份:2015
-
负责人:Thomas C. Sudhof
-
依托单位:
Control of long-term synaptic plasticity by neurexin ligands
-
批准号:8854549
-
项目类别:
-
资助金额:$35.57万
-
财政年份:2015
-
负责人:Thomas C. Sudhof
-
依托单位:
Analysis of human induced neuronal cells with and without psychosis high-risk mut
-
批准号:8925150
-
项目类别:
-
资助金额:$99.49万
-
财政年份:2015
-
负责人:Thomas C. Sudhof
-
依托单位:
Function of Neurexins
-
批准号:9220646
-
项目类别:
-
资助金额:$72.86万
-
财政年份:2015
-
负责人:Thomas C. Sudhof
-
依托单位:
Effects of psychosis high-risk mtations on mouse synaptic function
-
批准号:8743631
-
项目类别:
-
资助金额:$34.4万
-
财政年份:2014
-
负责人:Thomas C. Sudhof
-
依托单位:
Probing Alzheimer synaptopathy in neurons derived from engineered human iPS cells
-
批准号:8758446
-
项目类别:
-
资助金额:$200.63万
-
财政年份:2014
-
负责人:Thomas C. Sudhof
-
依托单位:
Analysis of human induced neuronal cells with and without psychosis high-risk mut
-
批准号:8743630
-
项目类别:
-
资助金额:$113.37万
-
财政年份:2014
-
负责人:Thomas C. Sudhof
-
依托单位:
Induced Neuronal Cells: A Novel Approach to Study Neuropsychiatric Diseases
-
批准号:8289641
-
项目类别:
-
资助金额:$41.48万
-
财政年份:2010
-
负责人:Thomas C. Sudhof
-
依托单位:
Induced neuronal cells: A novel tool to study neuropsychiatric diseases
-
批准号:10264112
-
项目类别:
-
资助金额:$74.84万
-
财政年份:2010
-
负责人:Thomas C. Sudhof
-
依托单位:
Direct conversion of fibroblasts into neurons: A novel approach to study neuropsy
-
批准号:8017238
-
项目类别:
-
资助金额:$44.29万
-
财政年份:2010
-
负责人:Thomas C. Sudhof
-
依托单位:
Induced neuronal cells: A novel tool to study neuropsychiatric diseases
-
批准号:8888299
-
项目类别:
-
资助金额:$68.09万
-
财政年份:2010
-
负责人:Thomas C. Sudhof
-
依托单位:
Induced Neuronal Cells: A Novel Approach to Study Neuropsychiatric Diseases
-
批准号:8662795
-
项目类别:
-
资助金额:$39.51万
-
财政年份:2010
-
负责人:Thomas C. Sudhof
-
依托单位:
海外基金