Latrophilin Function in Synapse Formation
Latrophilin 在突触形成中的功能
基本信息
- 批准号:10611452
- 负责人:
- 金额:$ 68.47万
- 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
- 起止时间:2021-07-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdhesionsAdhesivesAffectArchitectureArrestinsBehaviorBindingBinding SitesBiologicalBiological ModelsBrainBrain regionC-terminalCell Adhesion MoleculesCellsCognitionCognitiveCommunicationComplexCytoplasmDataExcitatory SynapseFamilyFunctional disorderG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGTP-Binding ProteinsGenesGoalsHeterozygoteHippocampusHomoHumanImpaired cognitionImpairmentInvestigationLifeLigand BindingLigandsMaintenanceMediatingMolecularMusMutationNatureNeuronsPathogenesisPlayProcessPropertyProtein IsoformsProteinsRoleShapesSignal PathwaySignal TransductionSignaling MoleculeSignaling ProteinSiteSpecific qualifier valueSpecificityStructureSynapsesSynaptic TransmissionTestingVentral Striatumalpha-latrotoxin receptorbehavioral studybiophysical analysiscognitive changeentorhinal cortexexperimental studyextracellularin vivoinsightinterdisciplinary approachinterestneural circuitneuropsychiatric disorderpostnatalpostsynapticreceptorsynaptic functionsynaptogenesistooltranslational 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.
神经回路由突触构成,突触将神经元连接成巨大的网络。虽然许多神经回路已经被表征,但构建其突触结构的分子和细胞机制在很大程度上仍然未知。在建立神经回路的突触结构的突触形成期间,经由跨突触粘附分子的双向信号传导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患神经精神疾病,这表明神经回路的突触结构功能障碍有助于神经精神疾病,尽管这些损伤的性质知之甚少。我们的初步数据表明,在海马神经元,兴奋性突触的子集的形成需要latrophilins(Lphns),一个家庭的三个突触后粘附-GPCR。不同的Lphns甚至在同一神经元中介导不同突触的建立,这表明它们不仅参与突触的构建,而且还参与决定它们的特异性。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,仍然是未知的。此外,人类Lphn 3基因(ADGRL 3)中的SNP强烈下调Lphn 3表达。本申请提出检查介导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Lphn 3表达的变化如何改变突触功能。具体而言,所提出的实验将测试以下总体假设:(1)Lphn通过涉及局部限制性信号传导的GPCR介导的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)Lphn 3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受损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采用广泛的跨学科方法,从配体-受体复合物的生物物理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,该应用将提供对Lphns如何驱动小鼠中的突触形成以及Lphn 3的表达减少如何倾向于人类神经元中的突触变化的洞察。解决这些问题在基础和转化神经科学中具有最重要的意义,因为处理大脑信息的神经回路是由突触形成构建的,并且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。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Engineered synaptic tools reveal localized cAMP signaling in synapse assembly.
- DOI:10.1083/jcb.202109111
- 发表时间:2022-02-07
- 期刊:
- 影响因子:0
- 作者:Sando R;Ho ML;Liu X;Südhof TC
- 通讯作者:Südhof TC
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
10434957 - 财政年份:2021
- 资助金额:
$ 68.47万 - 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:
$ 68.47万 - 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:
$ 68.47万 - 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:
$ 68.47万 - 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:
$ 68.47万 - 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:
$ 68.47万 - 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:
$ 68.47万 - 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:
$ 68.47万 - 项目类别:
相似海外基金
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y004841/1 - 财政年份:2024
- 资助金额:
$ 68.47万 - 项目类别:
Research Grant
Defining a role for non-canonical mTORC1 activity at focal adhesions
定义非典型 mTORC1 活性在粘着斑中的作用
- 批准号:
BB/Y001427/1 - 财政年份:2024
- 资助金额:
$ 68.47万 - 项目类别:
Research Grant
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y005414/1 - 财政年份:2024
- 资助金额:
$ 68.47万 - 项目类别:
Research Grant
Development of a single-use, ready-to-use, sterile, dual chamber, dual syringe sprayable hydrogel to prevent postsurgical cardiac adhesions.
开发一次性、即用型、无菌、双室、双注射器可喷雾水凝胶,以防止术后心脏粘连。
- 批准号:
10669829 - 财政年份:2023
- 资助金额:
$ 68.47万 - 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
- 批准号:
10587090 - 财政年份:2023
- 资助金额:
$ 68.47万 - 项目类别:
Improving Maternal Outcomes of Cesarean Delivery with the Prevention of Postoperative Adhesions
通过预防术后粘连改善剖宫产的产妇结局
- 批准号:
10821599 - 财政年份:2023
- 资助金额:
$ 68.47万 - 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
- 批准号:
10841832 - 财政年份:2023
- 资助金额:
$ 68.47万 - 项目类别:
Prevention of Intraabdominal Adhesions via Release of Novel Anti-Inflammatory from Surface Eroding Polymer Solid Barrier
通过从表面侵蚀聚合物固体屏障中释放新型抗炎剂来预防腹内粘连
- 批准号:
10532480 - 财政年份:2022
- 资助金额:
$ 68.47万 - 项目类别:
I-Corps: A Sprayable Tissue-Binding Hydrogel to Prevent Postsurgical Cardiac Adhesions
I-Corps:一种可喷雾的组织结合水凝胶,可防止术后心脏粘连
- 批准号:
10741261 - 财政年份:2022
- 资助金额:
$ 68.47万 - 项目类别:
Sprayable Polymer Blends for Prevention of Site Specific Surgical Adhesions
用于预防特定部位手术粘连的可喷涂聚合物共混物
- 批准号:
10674894 - 财政年份:2022
- 资助金额:
$ 68.47万 - 项目类别: