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是异质性的。收敛分子的鉴定 自闭症内表型的途径和神经回路对于发现新型药物靶标至关重要 用于开发有效的疗法。谷氨酸介导了大多数兴奋性神经传递 CNS。谷氨酸受体相互作用的蛋白1/2（Grip1/2）是神经元增强的脚手架蛋白，有7 PDZ域。 GRIP1/2的PDZ结构域4-6结合AMPA受体2/3（GLUA2/3）的C末端结构域。损失 小鼠中Grip1/2表达的表达导致神经元中GLUA2的回收延迟，社交性和提高 社交互动。 AMPA信号蛋白的研究确定了增强的GLUA2-S880磷酸化 突变小鼠的前额叶皮层。在自闭症患者的谷氨酸信号基因的屏幕中，我们发现 GRIP1-PDZ4-6的功能性突变有助于自闭症患者的社交相互作用减少。 为了研究GLUA2贩运的机制，以调节社会行为，我们产生了携带的敲门型小鼠 人类自闭症相关的突变I586L。 GRIP1-I586L小鼠与脑中Glua2的结合增加了 在经过修改的三腔社交测试中，裂解物并表现出降低的社交性。我们假设这一点 GRIP1-I586L改变GLUA2回收和表面表达，导致AMPA突触强度和 前额叶皮层中增强的局部连通性。我们将研究负责GLUA2的分子机制 GRIP1-KO和GRIP1-I586L小鼠的贩运缺陷。我们将研究神经机制 前额叶皮层中的AMPA信号传导，通过电生理学和 光遗传学方法。结果应提供对AMPA信号神经机制的宝贵见解 自闭症社会行为缺陷的缺陷。

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