Shank3 in Synaptic Function and Autism
Shank3 在突触功能和自闭症中的作用
基本信息
- 批准号:8890228
- 负责人:
- 金额:$ 40.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-01 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:22q13.3AffectAmygdaloid structureAreaAutistic DisorderBasal GangliaBehaviorBehavioralBindingBiological ModelsBrainBrain regionCandidate Disease GeneComplexCompulsive BehaviorCore ProteinCorpus striatum structureDLG4 geneDefectDevelopmentDiagnosisDopamine ReceptorEtiologyExhibitsFamilyFunctional Magnetic Resonance ImagingFunctional disorderGenesGeneticGenetic ScreeningGenomicsGlutamate ReceptorGlutamatesGoalsHumanImmediate-Early GenesImpairmentInterneuron functionInterneuronsKnockout MiceLeadLengthMediatingModelingMusMutant Strains MiceMutationNeurodevelopmental DisorderNeuronsNeurotransmittersNucleus AccumbensPathogenesisPathway interactionsPatientsPlayPrefrontal CortexProtein FamilyProteinsRelative (related person)ResearchRoleScaffolding ProteinSignal TransductionSocial InteractionStructureSynapsesSynaptic TransmissionSyndromeSystemThickVertebral columnViralautism spectrum disorderbehavioral impairmentcell typecholinergicdensityeffective therapyin vivomacromolecular assemblymemberneural circuitneurobehavioralneuromechanismnovel strategiesoptogeneticspostsynapticrare variantscaffoldselective expressionsocialsynaptic functiontrafficking
项目摘要
DESCRIPTION (provided by applicant): Recent genetic and genomic studies have identified a large number of candidate genes for autism spectrum disorders (ASDs), many of which encode synaptic proteins, suggesting synaptic dysfunction may play a critical role in ASDs. One of the most promising ASD candidate genes is Shank3. Shank family proteins (Shank1-3) directly bind SAPAP to form the PSD95/SAPAP/Shank complex. This core of proteins is thought to function as a scaffold, orchestrating the assembly of the macromolecular postsynaptic signaling complex. They have been proposed to play important roles in trafficking and anchoring of postsynaptic ionotropic glutamate receptors and the development of glutamatergic synapses. Shank3 is the only member of the Shank family highly expressed in the striatum, a brain region strongly implicated in ASDs. To investigate the in vivo function of Shank3 at synapses and to elucidate how a disruption of Shank3 may lead to ASDs, we generated Shank3 mutant mice. We found that disruption of Shank3 resulted in both structural and functional changes in cortico-striatal synapses. Furthermore, Shank3 mutant mice exhibit compulsive/repetitive behavior and impaired social interaction, which resemble two of the cardinal features of ASDs. Together, our studies demonstrate a critical role for Shank3 in cortico-striatal synaptic structure and function n vivo and establish causality between a disruption in the Shank3 gene and the genesis of autistic like-behaviors in mice. Thus, the Shank3 mutant mice provide us with an excellent opportunity to dissect the neural circuitry mechanisms underlying the abnormal behaviors relevant to human ASD. We propose to combine genetic, optogenetic, electrophysiological and behavioral approaches to achieve the following goals: (1) To investigate the intrastriatal microcircuitry dysfunction in Shank3 mutant mice. (2) To determine the relative contributions of the direct and indirect pathway of the basal ganglia in repetitive behavior. (3) To dissect neural circuits involved in social interaction deficits in Shank3 mutant mice. Together, these studies may significantly enhance our understanding of neural circuitry mechanisms of autistic-like behaviors and may help to develop novel strategies for more effective treatment.
描述(由申请人提供):最近的遗传和基因组研究已经确定了大量自闭症谱系障碍(ASD)的候选基因,其中许多基因编码突触蛋白,这表明突触功能障碍可能在ASD中起关键作用。最有希望的ASD候选基因之一是Shank 3。Shank家族蛋白(Shank 1 -3)直接结合SAPAP形成PSD 95/SAPAP/Shank复合物。这种蛋白质核心被认为是一种支架,协调大分子突触后信号复合物的组装。它们被认为在突触后离子型谷氨酸受体的运输和锚定以及谷氨酸能突触的发育中起重要作用。Shank 3是Shank家族中唯一在纹状体中高度表达的成员,纹状体是与ASD密切相关的大脑区域。为了研究Shank 3在突触中的体内功能并阐明Shank 3的破坏如何导致ASD,我们产生了Shank 3突变小鼠。我们发现Shank 3的破坏导致皮质-纹状体突触的结构和功能变化。此外,Shank 3突变小鼠表现出强迫/重复行为和受损的社会互动,这类似于ASD的两个主要特征。总之,我们的研究证明了Shank 3在体内皮质-纹状体突触结构和功能中的关键作用,并建立了Shank 3基因中断与小鼠自闭症样行为发生之间的因果关系。因此,Shank 3突变小鼠为我们提供了一个很好的机会来剖析与人类ASD相关的异常行为背后的神经回路机制。本研究拟将联合收割机、光遗传学、电生理学和行为学等方法相结合,实现以下目标:(1)研究Shank 3突变小鼠纹状体内微电路功能障碍。(2)确定基底神经节直接和间接通路在重复行为中的相对贡献。(3)解剖Shank 3突变小鼠中涉及社会互动缺陷的神经回路。总之,这些研究可能会显着提高我们对自闭症样行为的神经回路机制的理解,并可能有助于开发更有效的治疗新策略。
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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Guoping Feng其他文献
Guoping Feng的其他文献
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