AMPA receptor trafficking regulates social behaviors in autism
AMPA 受体贩运调节自闭症的社会行为
基本信息
- 批准号:9977799
- 负责人:
- 金额:$ 40.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-18 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AMPA ReceptorsAddressAffectAnimalsBehavioralBindingBiological AssayBiotinBrainC-terminalCandidate Disease GeneClinicalComplexCongenic StrainDefectDevelopmentElectrophysiology (science)EquilibriumEventExhibitsFunctional Magnetic Resonance ImagingGRIP1 geneGenesGlutamatesGrantHumanKineticsKnock-in MouseKnockout MiceLabelMedialMediatingMethodsModelingMolecularMusMutant Strains MiceMutationNeuronsNeurosciencesOpsinPathogenesisPathway interactionsPatientsPhenotypePhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPrefrontal CortexProteomicsRecyclingRegulationRoleScaffolding ProteinSignal TransductionSignaling ProteinSocial BehaviorSocial InteractionSurfaceSynapsesSynaptic TransmissionTestingTissuesTwo-Hybrid System TechniquesUpdateValidationWorkYeastsautism spectrum disorderbehavioral phenotypingdensityeffective therapyendophenotypegain of functiongain of function mutationglutamatergic signalinghippocampal pyramidal neuronin vivoinsightloss of functionmouse modelneural circuitneuromechanismneurotransmissionnew therapeutic targetnoveloptogeneticsprotein transportsocialsocial deficitstooltraffickingtwo photon microscopy
项目摘要
Abstract
Autism spectrum disorders are clinically and genetically heterogeneous. Identification of convergent molecular
pathways and neural circuits underlying autism endophenotypes are crucial to discovery of novel drug targets
for development of effective therapies. Glutamate mediates the majority of excitatory neurotransmission in the
CNS. Glutamate receptor interacting proteins 1/2 (GRIP1/2) are neuron-enriched scaffolding proteins with 7
PDZ domains. PDZ domains 4-6 of GRIP1/2 bind the c-terminal domain of AMPA receptor 2/3 (GluA2/3). Loss
of Grip1/2 expression in mice results in delayed recycling of GluA2 in neurons and increased sociability and
social interactions. Studies of AMPA-signaling proteins identified an enhanced GluA2-S880 phosphorylation in
prefrontal cortex in the mutant mice. In a screen of glutamate signaling genes in patients with autism, we found
gain-of-function mutations in GRIP1-PDZ4-6 that contribute to reduced social interactions in autism patients.
To study mechanisms of GluA2 trafficking in modulating social behaviors, we generated knock-in mice carrying
a human autism-associated mutation I586L. Grip1-I586L mice show increased binding with GluA2 in brain
lysates and exhibit a reduced sociability in the modified three-chamber sociability tests. We hypothesize that
Grip1-I586L alter GluA2 recycling and surface expression resulting in increased AMPA synaptic strength and
enhanced local connectivity in prefrontal cortex. We will study molecular mechanisms responsible for GluA2
trafficking defects in Grip1-KO and Grip1-I586L mice. We will investigate neural mechanisms of disturbance of
AMPA signaling in prefrontal cortex causing social behavioral deficits in autism using electrophysiology and
optogenetic methods. The results shall provide valuable insights into neural mechanisms of AMPA signaling
defects in social behavioral deficits in autism.
摘要
自闭症谱系障碍在临床和遗传上是异质性的。会聚分子的鉴定
孤独症内在表型的通路和神经回路对于发现新的药物靶点至关重要
开发有效的治疗方法。谷氨酸介导了大部分的兴奋性神经传递,
CNS。谷氨酸受体相互作用蛋白1/2(GRIP 1/2)是一种富含神经元的支架蛋白,
PDZ域。GRIP 1/2的PDZ结构域4-6结合AMPA受体2/3(GluA 2/3)的C末端结构域。损失
小鼠Grip 1/2表达的降低导致神经元中GluA 2的再循环延迟,并增加社交能力,
社交互动对AMPA信号蛋白的研究发现,
前额叶皮层的变化。在自闭症患者的谷氨酸信号基因筛选中,我们发现
GRIP 1-PDZ 4 -6中的功能获得性突变导致自闭症患者的社会互动减少。
为了研究GluA 2运输在调节社会行为中的机制,我们产生了携带GluA 2的基因敲入小鼠。
人类孤独症相关突变I586 L Grip 1-I586 L小鼠显示与脑中GluA 2的结合增加
裂解物,并在改良的三室社交性测试中表现出降低的社交性。我们假设
Grip 1-I586 L改变GluA 2再循环和表面表达,导致AMPA突触强度增加,
增强了前额叶皮层的局部连通性我们将研究负责GluA 2的分子机制
Grip 1-KO和Grip 1-I586 L小鼠的运输缺陷。我们将研究神经机制的干扰,
使用电生理学和神经电生理学研究导致自闭症患者社会行为缺陷的前额叶皮层AMPA信号传导
光遗传学方法。这些结果将为AMPA信号转导的神经机制提供有价值的见解
自闭症患者的社会行为缺陷
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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Richard L Huganir其他文献
Richard L Huganir的其他文献
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{{ truncateString('Richard L Huganir', 18)}}的其他基金
Development of kinase biosensors for multiplex neuronal imaging of signaling pathways in behaving mice
开发用于行为小鼠信号通路多重神经元成像的激酶生物传感器
- 批准号:
10505852 - 财政年份:2022
- 资助金额:
$ 40.88万 - 项目类别:
Developing Molecular and Computational Tools to Enable Visualization of Synaptic Plasticity In Vivo
开发分子和计算工具以实现体内突触可塑性的可视化
- 批准号:
10009886 - 财政年份:2020
- 资助金额:
$ 40.88万 - 项目类别:
AMPA receptor trafficking regulates social behaviors in autism
AMPA 受体贩运调节自闭症的社会行为
- 批准号:
9447811 - 财政年份:2017
- 资助金额:
$ 40.88万 - 项目类别:
AMPA receptor trafficking regulates social behaviors in autism
AMPA 受体贩运调节自闭症的社会行为
- 批准号:
10196966 - 财政年份:2017
- 资助金额:
$ 40.88万 - 项目类别:
Characterization of SynGAP Mutations in Human Cognitive Disorders
人类认知障碍中 SynGAP 突变的表征
- 批准号:
10094253 - 财政年份:2017
- 资助金额:
$ 40.88万 - 项目类别:
Characterization of SynGAP Mutations in Human Cognitive Disorders
人类认知障碍中 SynGAP 突变的表征
- 批准号:
9333783 - 财政年份:2017
- 资助金额:
$ 40.88万 - 项目类别:
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