Molecular Dissection of Active Zone Functions in Neurotransmitter Release
神经递质释放中活性区功能的分子剖析
基本信息
- 批准号:9275552
- 负责人:
- 金额:$ 37.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-07-01 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAddressAffectAnimal ModelArchitectureAutistic DisorderBindingBiochemicalBrainBrain DiseasesCaenorhabditis elegansCognitionCommunicationComplexDataDissectionDockingElectrophysiology (science)ElementsExocytosisGene FamilyGene StructureGenesGeneticGoalsHomologous GeneImageImpairmentIndividualInhibitory SynapseKnock-outKnockout MiceKnowledgeLeadLearningMeasurementMediatingModelingMolecularMorphologyNerveNerve DegenerationNeuronsPathologicPathway interactionsPhenotypeProbabilityProcessProteinsRecruitment ActivityRegulationResearchRoleSchizophreniaSignal TransductionSiteSpeedStructureSynapsesSynaptic TransmissionSynaptic VesiclesTestingVertebratesVesicleWorkaddictionchemical releasecontrolled releaseexperimental studygenetic approachinhibitor/antagonistinnovationinsightmutantnervous system disorderneural circuitneuronal circuitryneurotransmissionneurotransmitter releasenovelpresynapticpresynaptic neuronspublic health relevancescaffoldsynaptic functionsynaptogenesistooltransmission processvesicular release
项目摘要
DESCRIPTION (provided by applicant): Speed and precise regulation of synaptic transmission are critical for complex brain functions such as cognition and learning. Release of neurotransmitters from a presynaptic nerve terminal is often impaired in neurological disorders, including autism, schizophrenia, addiction and neurodegeneration. Exact knowledge of the molecular mechanisms for neurotransmitter release is thus critical for understanding brain disease. The active zone of a presynaptic nerve terminal is the site of neurotransmitter release. An active zone consists of a highly specialized network of proteins that organizes synaptic vesicles for fast Ca2+-triggering of release, a central requirement for speed and precision of synaptic transmission. It is our over-arching goal to understand how the protein machinery at the active zone operates. We approach this goal by dissecting the molecular functions of active zone components. ELKS proteins are highly enriched at active zones, indicating that ELKS functions in neuronal exocytosis at the active zone. Before release, active zones dock and prime synaptic vesicles for exocytosis close to presynaptic Ca2+-channels. How ELKS operates during these processes to control release is not understood, maybe in part because no systematic genetic approach has been taken in vertebrates to address ELKS function. We have now generated conditional knockout mice for both mammalian ELKS genes, ELKS1 and ELKS2. Ample preliminary data lead to our central hypothesis: ELKS proteins increase release probability though controlling presynaptic Ca2+-influx, and they modulate the size of the pool of readily releasable vesicles. We address separate components of this hypothesis in three specific aims, and we dissect the underlying molecular mechanisms. In aim 1, we hypothesize that ELKS1 and ELKS2 proteins have both shared and distinct functions. We determine how each ELKS gene contributes to the functions of active zones in neurotransmitter release by systematically studying presynaptic phenotypes in the newly generated conditional single knockout mice for ELKS1 and ELKS2, and in the ELKS1/2 double knockout mice. In preliminary experiments we find that ELKS proteins enhance presynaptic Ca2+-influx, and that individual and double ELKS deletions differentially affect the pool of readily releasable vesicles. In aim 2, we determine the mechanisms by which ELKS controls presynaptic Ca2+-influx. In aim 3, we propose a specific hypothesis that unifies effects on vesicle pools observed in ELKS mutants. We examine this hypothesis, determine the underlying molecular mechanisms and consider numerous alternative explanations. Our research is innovative because it addresses a novel hypothesis by a combination of genetic, biochemical and functional experiments of unique depth. Ultimately, this approach will lead to precise insights into the molecular control of neurotransmitter release, a key neuronal process that fails during various brain diseases.
描述(由申请人提供):突触传递的速度和精确调节对于认知和学习等复杂的大脑功能至关重要。神经递质从突触前神经末梢的释放通常在神经障碍中受损,包括自闭症、精神分裂症、成瘾和神经变性。因此,神经递质释放的分子机制的准确知识对于理解脑部疾病至关重要。突触前神经末梢的活动区是神经递质释放的场所。活性区由高度特化的蛋白质网络组成,其组织突触囊泡以快速Ca 2+触发释放,这是突触传递速度和精度的核心要求。我们的首要目标是了解活性区的蛋白质机制如何运作。我们通过解剖活性区组分的分子功能来实现这一目标。ELKS蛋白在活性区高度富集,表明ELKS在活性区的神经元胞吐中起作用。在释放前,活动区停靠并启动突触囊泡,以便靠近突触前Ca 2+通道进行胞吐。在这些过程中,ELKS如何控制释放尚不清楚,部分原因可能是因为在脊椎动物中没有系统的遗传方法来解决ELKS功能。我们现在已经产生了哺乳动物ELKS基因ELKS 1和ELKS 2的条件性敲除小鼠。充足的初步数据导致我们的中心假设:ELKS蛋白通过控制突触前Ca 2+内流增加释放概率,并且它们调节容易释放的囊泡池的大小。我们在三个特定的目标解决这个假设的单独组件,我们剖析了潜在的分子机制。在目标1中,我们假设ELKS 1和ELKS 2蛋白具有共同的和不同的功能。我们确定每个ELKS基因如何有助于神经递质释放的活性区的功能,通过系统地研究突触前表型在新产生的条件性单敲除小鼠ELKS 1和ELKS 2,并在ELKS 1/2双敲除小鼠。在初步的实验中,我们发现,ELKS蛋白增强突触前Ca 2+内流,和个别和双ELKS缺失差异影响池容易释放的囊泡。在目标2中,我们确定ELKS控制突触前Ca 2+内流的机制。在目标3中,我们提出了一个具体的假设,统一的影响囊泡池观察ELKS突变体。我们研究了这一假设,确定了潜在的分子机制,并考虑了许多替代解释。我们的研究是创新的,因为它通过独特深度的遗传,生化和功能实验的组合解决了一个新的假设。最终,这种方法将导致对神经递质释放的分子控制的精确见解,这是一个在各种脑部疾病中失败的关键神经元过程。
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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Pascal Simon Kaeser其他文献
Pascal Simon Kaeser的其他文献
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{{ truncateString('Pascal Simon Kaeser', 18)}}的其他基金
Mechanisms for somatodendritic dopamine release in the midbrain
中脑体细胞树突多巴胺释放机制
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10604832 - 财政年份:2023
- 资助金额:
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Architecture and function of striatal dopamine release machinery
纹状体多巴胺释放机制的结构和功能
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9402528 - 财政年份:2017
- 资助金额:
$ 37.08万 - 项目类别:
Architecture and function of striatal dopamine release machinery
纹状体多巴胺释放机制的结构和功能
- 批准号:
9528696 - 财政年份:2017
- 资助金额:
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Architecture and function of striatal dopamine signaling machinery
纹状体多巴胺信号机制的结构和功能
- 批准号:
10464718 - 财政年份:2017
- 资助金额:
$ 37.08万 - 项目类别:
Dissecting the assembly of neurotransmitter release sites
剖析神经递质释放位点的组装
- 批准号:
10682464 - 财政年份:2017
- 资助金额:
$ 37.08万 - 项目类别:
Dissecting the assembly of neurotransmitter release sites
剖析神经递质释放位点的组装
- 批准号:
10536772 - 财政年份:2017
- 资助金额:
$ 37.08万 - 项目类别:
Architecture and Function of Striatal Dopamine Signaling Machinery
纹状体多巴胺信号传导机制的结构和功能
- 批准号:
10589076 - 财政年份:2017
- 资助金额:
$ 37.08万 - 项目类别:
Dissecting the assembly of vertebrate neurotransmitter release sites-Research Supplements to Promote Diversity in Health-Related Research
剖析脊椎动物神经递质释放位点的组装——促进健康相关研究多样性的研究补充
- 批准号:
9896449 - 财政年份:2017
- 资助金额:
$ 37.08万 - 项目类别:
Architecture and function of striatal dopamine release machinery
纹状体多巴胺释放机制的结构和功能
- 批准号:
9915988 - 财政年份:2017
- 资助金额:
$ 37.08万 - 项目类别:
Molecular Dissection of Active Zone Functions in Neurotransmitter Release
神经递质释放中活性区功能的分子剖析
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10613501 - 财政年份:2014
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