Examining striatal synaptic function across mouse models of autism spectrum disorder (ASD)

检查自闭症谱系障碍 (ASD) 小鼠模型的纹状体突触功能

• 批准号: 10620187
• 负责人: Katie Cording
• 金额: $ 4.45万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620187
• 关键词: Acceleration; Affect; Basal Ganglia; Behavior; Behavioral; Biological Assay; Brain region; Cell Adhesion Molecules; Cells; Code; Corpus striatum structure; Data; Disease; Dopamine D1 Receptor; Dopamine D2 Receptor; Electrophysiology (science); Exhibits; FRAP1 gene; Functional disorder; Gene Family; Gene Mutation; Genetic; Goals; Habits; Human; Impairment; Learning; Link; Measures; Modeling; Motor; Mus; Mutation; Neurodevelopmental Disorder; Neurons; Operant Conditioning; Outcome; Output; Pathway interactions; Pattern; Performance; Phosphoric Monoester Hydrolases; Physiological; Physiology; Property; Proteins; Proto-Oncogene Proteins c-akt; Proxy; Research; Role; Signal Transduction; Site; Slice; Social Interaction; Sodium Channel; Structure; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; TSC1 gene; Testing; Therapeutic; Therapeutic Intervention; Work; autism spectrum disorder; cell type; design; diagnostic criteria; disease classification; experimental study; habit learning; individuals with autism spectrum disorder; insight; inward rectifier potassium channel; motor behavior; motor learning; mouse model; neuronal excitability; optogenetics; repetitive behavior; risk variant; social; social communication; synaptic function; targeted treatment; voltage

ABSTRACT Autism spectrum disorder (ASD) is a neurodevelopmental disorder classified by two major diagnostic criteria - persistent deficits in social communication and interaction, and the presence of restricted, repetitive patterns of behavior. The striatum, the main input center of the basal ganglia, has been implicated in the presentation of repetitive behaviors given its roles in action selection, motor learning and habit formation. Despite clear links between striatal functions and ASD-related behavioral alterations, the striatum, and basal ganglia in general, remain relatively underexplored in ASD research. Recent work from our lab and others has shown that striatal cell type-specific deletion of ASD risk genes in mice is sufficient to increase performance on the accelerating rotarod task, a striatum-dependent motor learning assay used as a proxy for acquired repetitive behaviors. We further showed that this enhanced motor learning is associated with increased corticostriatal excitatory connectivity. Together this work suggests that enhanced corticostriatal drive may promote the acquisition of fixed motor routines in the context of ASD-related genetic perturbations. In this proposal, I will test the hypothesis that striatal, in particular corticostriatal, connectivity and synaptic plasticity is commonly altered across mouse models of ASD that harbor mutations in a range of risk genes. In addition, I will determine how mutations in ASD-risk genes impact striatal-dependent motor and habit learning. I will focus on three mouse models of autism, with disruption in ASD-risk genes that code for a range of protein types: Cntnap2, which codes for a synaptic adhesion molecule, Pten, which codes for phosphatase that negatively regulates AKT and mTOR signaling, and Scn2a, which codes for a voltage-gated sodium channel. I will determine the potential alterations in striatum-dependent behaviors in these models by utilizing behavior assays that assess learned motor behaviors thought to be dependent on corticostriatal synaptic transmission. I will then assess the impact of these mutations on the physiological properties of spiny projection neurons (SPNs), the main output cells of the striatum, and attempt to rescue alterations in habitual motor behaviors by modifying SPN excitability. These experiments will increase our understanding of how striatal pathophysiology contributes to ASD and may identify points of convergence at the synaptic or circuit level that are shared across genetically diverse forms of ASD. Such an outcome may enable the design of therapeutics that can restore striatal function in the context of ASD.

抽象的 自闭症谱系障碍（ASD）是一种由两个主要诊断标准分类的神经发育障碍 - 社会交流和互动中的持续缺陷，以及存在受限制的重复模式的存在 行为。纹状体是基底神经节的主要输入中心，与表示 重复行为鉴于其在动作选择，运动学习和习惯形成中的作用。尽管有明确的链接 纹状体功能和与ASD相关的行为改变，纹状体和基底神经节之间 在ASD研究中，保持相对不受欢迎。我们实验室和其他人的最新工作表明纹状体 小鼠中ASD风险基因的细胞类型特异性缺失足以提高加速性能 rotarod任务，一种依赖于纹状体的运动学习测定法，用作获得的重复行为的代理。我们 进一步表明，这种增强的运动学习与皮质纹状体兴奋性增加有关 连接性。这项工作共同表明增强的皮质纹状体驱动可能会促进固定的获取 在与ASD相关的遗传扰动背景下的运动例程。 在此提案中，我将检验以下假设：纹状体，特别是皮质纹状体，连通性和突触 在一系列风险基因中藏有突变的ASD小鼠模型中，通常会改变可塑性。在 此外，我还将确定ASD风险基因中的突变如何影响依赖纹状体的运动和习惯学习。我 将重点放在三种自闭症的鼠标模型上，并在ASD风险基因中破坏，以编码一系列蛋白质 类型：编码突触粘附分子PTEN的CNTNAP2，它代码为磷酸酶编码 负调控AKT和MTOR信号传导和SCN2A，该信号代码为电压门控钠通道。我 将通过使用行为来确定这些模型中纹状体依赖性行为的潜在改变 评估学到的运动行为的测定法被认为取决于皮质纹状体突触传播。我 然后，将评估这些突变对刺刺神经元（SPNS）的生理特性的影响， 纹状体的主要输出单元格，并试图通过修改习惯运动行为的改变 SPN兴奋性。这些实验将增加我们对纹状体病理生理学如何贡献的理解 到ASD并可能识别在遗传上共享的突触或电路水平上收敛点 ASD的各种形式。这样的结果可以使可以恢复纹状体功能的治疗剂设计 在ASD的背景下。