Function of Neurexins
神经毒素的功能
基本信息
- 批准号:8932978
- 负责人:
- 金额:$ 71.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-03-15 至 2020-02-29
- 项目状态:已结题
- 来源:
- 关键词:AddressAffinityAlternative SplicingAnimal ModelAutistic DisorderBiochemicalBrainCell Adhesion MoleculesCellsCodeCommunicationDiseaseElectrophysiology (science)Functional disorderFundingGene ExpressionGenerationsGenesGeneticGoalsHuman GeneticsImageImpairmentInstructionInvestmentsLigandsLinkMapsMediatingMessenger RNAMethodsMusMutateMutationNeuronsPatternPeriod AnalysisPhenotypePlasticsProcessProgress ReportsPropertyProtein ChemistryProtein IsoformsProteinsRNA SplicingRelative (related person)Reverse Transcriptase Polymerase Chain ReactionRoleSchizophreniaSiteSpecific qualifier valueSynapsesSynaptic TransmissionTechnologyTestingTimeWorkbehavioral studycell typeexperiencegene functiongenetic analysisinformation processinginsightmutantneural circuitneuropsychiatrynovelpostsynapticpresynapticprotein protein interactionresearch studysynaptic functionsynaptogenesis
项目摘要
Although enormous progress has been achieved in understanding how synapses work, little is known about how synapses are formed, and how diverse synapse properties are specified. Recent work suggests that neurexins have a central role in synapse specification, and that mutations in genes encoding neurexins contribute to autism and schizophrenia. Neurexins are presynaptic cell-adhesion molecules that are essential for normal synapse function, interact with multiple of postsynaptic ligands which in turn have also been implicated in autism and schizophrenia, and are expressed in thousands of alternatively spliced, regulated isoforms. The overarching goal of the present project is to elucidate the basic cellular and circuit functions of neurexins in mice as a model organism in order to gain insight into how neurexins contribute to the ability of synapses to transmit information, and to promote the understanding of how impairments in neurexin functions predispose to neuropsychiatric disorders. The project proposes five specific aims, namely to elucidate the trans-synaptic protein interaction network mediated by neurexins (Specific Aim 1), to determine the experience-dependent patterns of neurexin alternative splicing in defined types of neurons at the single-cell level (Specific Aim 2), to elucidate the role of alternative splicing of neurexins at SS#4 (Specific Aim 3), to determine the relative functions of neurexins using cKO mice (Specific Aim 4), and to perform an initial definition of the mechanisms of neurexin function. These specific aims will be pursued using an interdisciplinary combination of methods that prominently include mouse genetics, electrophysiology, gene expression studies, imaging, and protein chemistry. The specific aims are complementary to each other, and their results will synergize in producing a description of neurexins that relates the interactions of neurexins with specific pre- and postsynaptic ligands to their neuronal cell type-specific and activity-dependent expression, their alternative splicing, and their diverse functions. In this manner, this project will not only contribute to our basic understanding of how synapses process information in neural circuits, but also
provide insight into how neurexin dysfunction contributes to neuropsychiatric disorders.
RELEVANCE (See instructions):
Major recent progress revealed that the presynaptic cell-adhesion molecules neurexins and their ligands are genetically linked to autism, schizophrenia, and other neuropsychiatric disorders, but the basic functions of these molecules and the consequences of their dysfunction are incompletely understood. In addressing these issues, the present project will illuminate the pathogenic mechanisms underlying these disorders.
尽管在理解突触如何工作方面取得了巨大的进展,但对突触如何形成以及突触的不同特性是如何指定的知之甚少。最近的研究表明,神经毒素在突触规范中起着核心作用,编码神经毒素的基因突变导致了自闭症和精神分裂症。神经素是突触前细胞粘附分子,对正常突触功能至关重要,与多种突触后配体相互作用,而这些配体反过来也与自闭症和精神分裂症有关,并以数千种选择性剪接、受调节的同种异构体表达。本项目的总体目标是阐明作为模型生物的小鼠神经xin素的基本细胞和电路功能,以便深入了解神经xin素如何促进突触传递信息的能力,并促进对神经xin素功能损伤如何易患神经精神疾病的理解。该项目提出了五个特定目标,即阐明由神经毒素介导的跨突触蛋白相互作用网络(specific Aim 1),确定单细胞水平上特定类型神经元中神经毒素选择性剪接的经验依赖模式(specific Aim 2),阐明神经毒素选择性剪接在SS#4中的作用(specific Aim 3),确定使用cKO小鼠的神经毒素的相对功能(specific Aim 4),并对神经素的功能机制进行初步定义。这些具体目标将采用跨学科的方法,包括小鼠遗传学、电生理学、基因表达研究、成像和蛋白质化学。具体目标是相互补充的,它们的结果将协同产生神经毒素的描述,将神经毒素与特定突触前和突触后配体的相互作用与神经元细胞类型特异性和活性依赖性表达,它们的替代剪接和它们的多种功能联系起来。通过这种方式,这个项目不仅有助于我们对突触如何在神经回路中处理信息的基本理解,而且还将有助于我们对神经回路中突触如何处理信息的理解
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Thomas C. Sudhof其他文献
Single piconewton forces regulate dissociation of the Latrophilin-3 gain domain
- DOI:
10.1016/j.bpj.2022.11.696 - 发表时间:
2023-02-10 - 期刊:
- 影响因子:
- 作者:
Brian L. Zhong;Christina E. Lee;Vipul T. Vachharajani;Thomas C. Sudhof;Alexander R. Dunn - 通讯作者:
Alexander R. Dunn
Presynaptic Neurexin-3 Alternative Splicing Trans-Synaptically Controls Postsynaptic AMPA-Receptor Traficking
突触前 Neurexin-3 选择性剪接跨突触控制突触后 AMPA 受体运输
- DOI:
- 发表时间:
- 期刊:
- 影响因子:64.5
- 作者:
Jason Aoto;David C Martinelli;Robert C Malenka;Katsuhiko Tabuchi;Thomas C. Sudhof - 通讯作者:
Thomas C. Sudhof
Thomas C. Sudhof的其他文献
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{{ truncateString('Thomas C. Sudhof', 18)}}的其他基金
Latrophilin Function in Synapse Formation
Latrophilin 在突触形成中的功能
- 批准号:
10611452 - 财政年份:2021
- 资助金额:
$ 71.63万 - 项目类别:
Latrophilin Function in Synapse Formation
Latrophilin 在突触形成中的功能
- 批准号:
10434957 - 财政年份:2021
- 资助金额:
$ 71.63万 - 项目类别:
Regulation of cholesterol by y-secretase and ApoE: Implications for AD pathogenesis and synaptic function
γ-分泌酶和 ApoE 对胆固醇的调节:对 AD 发病机制和突触功能的影响
- 批准号:
10601030 - 财政年份:2021
- 资助金额:
$ 71.63万 - 项目类别:
Regulation of cholesterol by y-secretase and ApoE: Implications for AD pathogenesis and synaptic function
γ-分泌酶和 ApoE 对胆固醇的调节:对 AD 发病机制和突触功能的影响
- 批准号:
10379401 - 财政年份:2021
- 资助金额:
$ 71.63万 - 项目类别:
Latrophilin Function in Synapse Formation
Latrophilin 在突触形成中的功能
- 批准号:
10274019 - 财政年份:2021
- 资助金额:
$ 71.63万 - 项目类别:
The role of Myt1l in the developing and adult mouse brain
Myt1l 在发育中和成年小鼠大脑中的作用
- 批准号:
9904331 - 财政年份:2019
- 资助金额:
$ 71.63万 - 项目类别:
The role of Myt1l in the developing and adult mouse brain
Myt1l 在发育中和成年小鼠大脑中的作用
- 批准号:
10579921 - 财政年份:2019
- 资助金额:
$ 71.63万 - 项目类别:
The role of Myt1l in the developing and adult mouse brain
Myt1l 在发育中和成年小鼠大脑中的作用
- 批准号:
10333320 - 财政年份:2019
- 资助金额:
$ 71.63万 - 项目类别:
Control of long-term synaptic plasticity by neurexin ligands
神经毒素配体控制长期突触可塑性
- 批准号:
8854549 - 财政年份:2015
- 资助金额:
$ 71.63万 - 项目类别:
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