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.

摘要 自闭症谱系障碍在临床和遗传上是不同的。收敛分子的鉴定 孤独症内表型的通路和神经回路是发现新的药物靶点的关键 用于开发有效的治疗方法。谷氨酸介导了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)是一种神经元丰富的支架蛋白，具有7 PDZ域。GRIP1/2的PDZ结构域4-6与AMPA受体2/3(GluA2/3)的c-末端结构域结合。损失 小鼠Grig1/2的表达导致神经元中GluA2的延迟再循环，并增加了社交能力和 社交互动。AMPA信号转导蛋白的研究证实GluA2-S880磷酸化增强 突变小鼠的前额叶皮质。在对自闭症患者谷氨酸信号基因的筛选中，我们发现 导致自闭症患者社交互动减少的GRIP1-PDZ4-6功能获得突变。 为了研究GluA2转运调节社会行为的机制，我们产生了携带GluA2的敲入小鼠 人类自闭症相关突变I586L。GRIP1-I586L小鼠与脑内GluA2的结合增加 在改进的三室社交测试中，溶质和表现出的社交能力降低。我们假设 Grig1-I586L改变GluA2的循环和表面表达，导致AMPA突触强度增加和 增强了前额叶皮质的局部连接。我们将研究GluA2的分子机制 GRIP1-KO和GRIP1-I586L小鼠的运输缺陷。我们将研究精神障碍的神经机制。 前额叶皮质AMPA信号导致自闭症患者社会行为缺陷的电生理学和临床研究 光遗传学方法。这些结果将为研究AMPA信号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

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

• DOI: 10.1038/s41398-020-01194-6
• 发表时间: 2021-01-18
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Mejias R;Rodriguez-Gotor JJ;Niwa M;Krasnova IN;Adamczyk A;Han M;Thomas GM;Xi ZX;Huganir RL;Pletnikov MV;Sawa A;Cadet JL;Wang T
• 通讯作者: Wang T