Exploring the mechanisms of Semaphorin/Plexin-mediated synapse formation in the intact hippocampus
探索完整海马中 Semaphorin/Plexin 介导的突触形成机制
基本信息
- 批准号:10373966
- 负责人:
- 金额:$ 3.54万
- 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:2021-03-16 至 2023-03-15
- 项目状态:已结题
- 来源:
- 关键词:AdultAffinityAlzheimer&aposs DiseaseAttentionBiological AssayBrainCD100 antigenCell CommunicationCell physiologyCellsChimera organismClinicalCognition DisordersComplexCytoskeletal ModelingDataDevelopmentDown SyndromeERBB2 geneEphrinsEpilepsyExcitatory SynapseExhibitsExtracellular DomainFamilyGenesGlutamatesHeterodimerizationHippocampus (Brain)HomoImaging technologyInhibitory SynapseIon Channel GatingKnock-outKnockout MiceLigandsLinkMediatingMental disordersModelingMolecularMolecular ConformationMusNervous system structureNeuraxisNeurodegenerative DisordersNeurogliaNeurotransmittersPathway interactionsPharmacologyPlayProcessPropertyProtein FamilyProteinsRNA InterferenceReceptor Protein-Tyrosine KinasesRecombinantsResearchRodentRoleSEMA3F geneScaffolding ProteinSeizuresSemaphorinsSignal PathwaySignal TransductionSliceSpecific qualifier valueSynapsesSynaptic VesiclesTestingTimeTo specifyTransgenic MiceTransmembrane DomainWorkautism spectrum disorderaxon guidancecell typedensitydevelopmental neurobiologyexcitatory neuronexperimental studyforward geneticsgamma-Aminobutyric Acidgene discoverygenetic manipulationgenome-widehigh resolution imagingin vivoinhibitorinhibitory neuronknock-downmutantnervous system developmentnoveloverexpressionplexinpostsynapticpostsynaptic neuronspresynapticreceptorresilienceresponsereverse geneticssynaptic functionsynaptogenesistool
项目摘要
Project Summary:
In the mammalian central nervous system, two main types of synapses – glutamatergic and GABAergic – play
opposing roles in exciting or inhibiting the postsynaptic cell. While it is critical that upon cell-cell contact, new
synapses form the correct postsynaptic specialization (excitatory or inhibitory), the molecular pathways
specifying this identity remain a fundamental mystery in developmental neurobiology. This process is
presumably regulated by trans-synaptic ligand/receptor partners that belong to protein families (e.g.
Neuroligins/Neurexins, Ephrins/Ephs, Semaphorins/Plexins) which have been demonstrated to regulate both
excitatory and inhibitory synapse formation.
Semaphorins (Semas) and Plexins are families of widely expressed and functionally versatile transmembrane or
secreted ligands and their transmembrane receptors that first gained attention for their roles in axon guidance
during nervous system development. Class 4 Semas and Plexin-B receptors are expressed in mammalian
hippocampus (in excitatory and inhibitory neurons and in glia) and promote synapse formation both during
development and in adulthood.
Our previous studies revealed Sema4D to be one of few molecules having synaptogenic function restricted to
inhibitory synapses; the extracellular domain of Sema4D induces inhibitory synapse formation on a rapid
timescale (~30 mins) through the Plexin-B1 receptor. Additionally, Sema4A promotes formation of both
inhibitory and excitatory synapses in hippocampus via the Plexin-B1 or Plexin-B2 receptors, respectively. The
ability to rapidly drive synapse formation by application of Sema4A or Sema4D, as well as the observations that
these Semas regulate inhibitory and excitatory synapse formation in unique ways requiring different Plexin-B
receptors, are central to our proposed strategy to identify the distinct signaling conformations that
instruct synapse identity (excitatory or inhibitory) downstream of Plexin-B receptor
engagement. Further, we previously showed that Sema4D protein application increases
resilience to seizure in adult mice in vivo, a finding that supports the potential clinical impact of
this work.
The proposed research uses a combination of transgenic mice, organotypic hippocampal slice culture, gene
knockdown, and expression of mutant forms of Plexin-B receptors to examine the divergent roles of 1) unique
Plexin-B signaling domains, 2) a novel mechanism gating Plexin-B1 signaling in cis, and 3) contributions from
Plexin-B coreceptors, in excitatory and inhibitory synapse formation promoted by class 4 semaphorins.
项目总结:
在哺乳动物中枢神经系统中,两种主要类型的突触-谷氨酸能和GABA能-发挥作用
在刺激或抑制突触后细胞中扮演相反的角色。虽然在细胞-细胞接触时,新的
突触形成正确的突触后特化(兴奋性或抑制性),即分子通路
确定这一身份仍然是发育神经生物学中的一个基本谜团。这个过程是
推测是由属于蛋白质家族的跨突触配体/受体伙伴调节的。
神经连接蛋白/Neurexins、Eparins/Ephs、信号素/丛蛋白),它们已被证明调节两者
兴奋性和抑制性突触形成。
信号素(Sema)和丛状蛋白(Plexin)是广泛表达和功能多样的跨膜蛋白家族
分泌型配体及其跨膜受体首次因其在轴突引导中的作用而受到关注
在神经系统发育过程中。4类Semas和Plexin-B受体在哺乳动物中的表达
海马体(在兴奋性和抑制性神经元以及神经胶质细胞中)和促进突触的形成
发展阶段和成年阶段。
我们之前的研究表明Sema4D是少数几个具有突触发生功能的分子之一
抑制性突触;Sema4D的胞外区诱导快速的抑制性突触形成
时间刻度(~30分钟)通过丛状蛋白-B1受体。此外,Sema4a促进两者的形成
海马区的抑制性突触和兴奋性突触分别通过丛蛋白-B1和丛蛋白-B2受体。这个
通过应用Sema4a或Sema4D快速驱动突触形成的能力,以及观察到的
这些SIMA以独特的方式调节抑制性和兴奋性突触的形成,需要不同的神经丛-B
受体,是我们提出的识别不同信号构象的核心策略
指示神经丛蛋白-B受体下游的突触识别(兴奋性或抑制性)
订婚。此外,我们先前表明Sema4D蛋白的应用增加了
成年小鼠在活体内对癫痫发作的弹性,这一发现支持了阿司匹林对癫痫的潜在临床影响
这项工作。
建议的研究使用了转基因小鼠、器官型海马片培养、基因
敲除和表达突变型的丛蛋白-B受体以研究1)独特的不同作用
Plexin-B信号域,2)在顺式系统中调节Plexin-B1信号的新机制,以及3)来自
4类信号素促进兴奋性和抑制性突触形成的丛蛋白-B辅助受体。
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)
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