Establishing the cohort of early active zone proteins and their role in synaptic strength and maturation at the Drosophila neuromuscular junction.
建立早期活性区蛋白群体及其在果蝇神经肌肉接头突触强度和成熟中的作用。
基本信息
- 批准号:10462313
- 负责人:
- 金额:$ 4.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-07 至 2025-09-06
- 项目状态:未结题
- 来源:
- 关键词:Action PotentialsAgeAmino AcidsAnimalsAutomobile DrivingAutophagocytosisBindingBiological AssayBiological ModelsBrainC2 DomainCRISPR screenCalciumCalcium ChannelCell physiologyChargeCoiled-Coil DomainComplementConfocal MicroscopyDataDefectDepositionDevelopmentDiseaseDrosophila genusDrosophila melanogasterElectric StimulationEndocytosisEventExcitatory SynapseFunctional disorderGlutamate ReceptorGlutamatesGuide RNAHourHumanHuman DevelopmentImageIndividualInstitutesIntellectual functioning disabilityLeadLearningLipid BindingLipidsMassachusettsMeasuresMediatingMembraneMemoryModelingMolecularMotor NeuronsNeurodevelopmental DisorderNeuromuscular JunctionNeuronsOpticsOutputPathway interactionsPhosphoric Monoester HydrolasesPhosphotransferasesPlayPostsynaptic MembraneProbabilityProcessProteinsResearchResolutionRoleScaffolding ProteinSeedsSiteStretchingSynapsesSynaptic MembranesSynaptic TransmissionSynaptic VesiclesTechnologyTrainingWorkactive controlautism spectrum disorderbrain dysfunctioncohortconfocal imagingdensityexperimental studyfluorescence imaginggenetic approachinsightloss of functionneurotransmissionnoveloverexpressionpostsynapticpresynapticpresynaptic neuronspreventprotein transportquantumreceptorscaffoldsensortraffickingvesicular releasevoltage
项目摘要
PROJECT SUMMARY/ABSTRACT
Presynaptic active zones (AZs) cluster synaptic vesicle (SV) fusion machinery across from postsynaptic receptor
fields, facilitating efficient neural signaling. Proper development of glutamatergic synapses and AZs is critical for
normal mammalian brain development. These synapses are involved in learning and memory and their
dysfunction causes neurodevelopmental disorders like intellectual disability and autism spectrum disorder.
However, the development and maturation of these AZs is poorly understood. Drosophila melanogaster larval
motor neurons form many AZs which serve as a genetically and experimentally tractable model for mammalian
glutamatergic synapses. Previous work at the Drosophila neuromuscular junction (NMJ) has established that AZ
material accumulates in two steps: early in AZ development, proteins such as Syd-1, Liprin-a, and Unc-13B form
an initial release scaffold and Brp, Cac (Drosophila voltage-gated calcium channel), RIM and Unc-13A arrive
hours later. AZ age and incorporation of the late components Brp and Cac correlate with maturation and synaptic
vesicle release probability (Pr) at individual AZs. The contribution of the early scaffolds to synaptic strength and
AZ maturation is an open question. In addition, the full cohort of early proteins that can contribute to AZ seeding
and maturation is unknown. In Aim 1, structural and functional maturity of individual AZs will be assessed
following depletion and overexpression of early AZ scaffolds. Accumulation of fluorescently tagged Glutamate
receptor (GluR) subunits will be measured throughout development using high resolution confocal imaging of
live animals. At mature AZs, GluRIIA and GluRIIB subunits segregate into distinct rings. Levels of presynaptic
Brp and Cac at individual AZs will also be quantified to assess structural maturity. Functional maturity of individual
AZs will be assessed by calculating Pr. Using a fluorescent calcium sensor attached to the postsynaptic
membrane, individual SV fusion events following electrical stimulation are visualized by calcium entry through
GluRs. In Aim 2, proteins which contribute to formation and maturation of the AZ will be identified using a
CRISPR-based screen in single neurons. Many currently identified AZ proteins have lipid binding domains which
may bind specific regions of synaptic membrane rich in individual lipid species. Lipid kinases and phosphatases
will be eliminated in single neurons with Cas9 in order to identify disruptions in AZ formation and maturation.
These experiments are made possible by experimental approaches only available in Drosophila, but will provide
insights relevant to human neurodevelopmental disease and glutamatergic synapse development. All of the work
and prerequisite training to accomplish these Aims will be performed at Massachusetts Institute of Technology
in Dr. Troy Littleton’s lab.
项目总结/文摘
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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Ellen Guss其他文献
Ellen Guss的其他文献
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{{ truncateString('Ellen Guss', 18)}}的其他基金
Establishing the Cohort of Early Active Zone Proteins and their Role in Synaptic Strength and Maturation at the Drosophila Neuromuscular Junction
建立早期活性区蛋白群体及其在果蝇神经肌肉接头突触强度和成熟中的作用
- 批准号:
10615711 - 财政年份:2022
- 资助金额:
$ 4.68万 - 项目类别:
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