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
• 负责人: Richard L Huganir
• 金额: $ 40.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196966
• 关键词: AMPA Receptors; Address; Affect; Animals; Behavioral; Binding; Biological Assay; Biotin; Brain; C-terminal; Candidate Disease Gene; Clinical; Complex; Congenic Strain; Defect; Development; Electrophysiology (science); Equilibrium; Event; Exhibits; Functional Magnetic Resonance Imaging; GRIP1 gene; Genes; Glutamates; Grant; Human; Kinetics; Knock-in Mouse; Knockout Mice; Label; Medial; Mediating; Methods; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Neurons; Neurosciences; Opsin; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Prefrontal Cortex; Proteomics; Recycling; Regulation; Role; Scaffolding Protein; Signal Transduction; Signaling Protein; Social Behavior; Social Interaction; Surface; Synapses; Synaptic Transmission; Testing; Tissues; Two-Hybrid System Techniques; Update; Validation; Work; Yeasts; autism spectrum disorder; behavioral phenotyping; density; effective therapy; endophenotype; gain of function; gain of function mutation; glutamatergic signaling; hippocampal pyramidal neuron; in vivo; insight; loss of function; mouse model; neural circuit; neuromechanism; neurotransmission; new therapeutic target; novel; optogenetics; protein transport; social; social deficits; tool; trafficking; two photon microscopy

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.

抽象的 自闭症谱系障碍在临床和遗传上具有异质性。聚合分子的鉴定 自闭症内表型背后的通路和神经回路对于发现新的药物靶点至关重要 以开发有效的疗法。谷氨酸介导大部分兴奋性神经传递 中枢神经系统。谷氨酸受体相互作用蛋白 1/2 (GRIP1/2) 是富含神经元的支架蛋白，具有 7 PDZ 域。 GRIP1/2 的 PDZ 结构域 4-6 结合 AMPA 受体 2/3 (GluA2/3) 的 c 端结构域。损失 小鼠中 Grip1/2 表达的降低会导致神经元中 GluA2 的循环延迟，并增加社交性和 社交互动。 AMPA 信号蛋白的研究发现，GluA2-S880 磷酸化增强 突变小鼠的前额皮质。在对自闭症患者谷氨酸信号基因的筛选中，我们发现 GRIP1-PDZ4-6 的功能获得性突变导致自闭症患者的社交互动减少。 为了研究 GluA2 贩运调节社会行为的机制，我们培育了携带 人类自闭症相关突变 I586L。 Grip1-I586L 小鼠大脑中与 GluA2 的结合增加 裂解物并在改良的三室社交性测试中表现出社交性降低。我们假设 Grip1-I586L 改变 GluA2 循环和表面表达，导致 AMPA 突触强度增加， 增强前额皮质的局部连接。我们将研究负责 GluA2 的分子机制 Grip1-KO 和 Grip1-I586L 小鼠的运输缺陷。我们将研究干扰的神经机制 使用电生理学和方法研究前额皮质中的 AMPA 信号导致自闭症的社会行为缺陷 光遗传学方法。结果将为 AMPA 信号传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

Mice lacking GRIP1/2 show increased social interactions and enhanced phosphorylation at GluA2-S880.

缺乏 GRIP1/2 的小鼠表现出社交互动增加和 GluA2-S880 磷酸化增强。

• 发表时间: 2017
• 影响因子: 2.7
• 作者: Han, Mei;Mejias, Rebeca;Chiu, Shu;Rose, Rebecca;Adamczyk, Abby;Huganir, Richard;Wang, Tao
• 通讯作者: Wang, Tao

Increased novelty-induced locomotion, sensitivity to amphetamine, and extracellular dopamine in striatum of Zdhhc15-deficient mice.

Zdhhc15 缺陷小鼠纹状体中新奇诱导的运动、对安非他明和细胞外多巴胺的敏感性增加。

• 发表时间: 2021
• 影响因子: 6.8
• 作者: Mejias, Rebeca;Rodriguez;Niwa, Minae;Krasnova, Irina N;Adamczyk, Abby;Han, Mei;Thomas, Gareth M;Xi, Zheng;Huganir, Richard L;Pletnikov, Mikhail V;Sawa, Akira;Cadet, Jean;Wang, Tao
• 通讯作者: Wang, Tao