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.

摘要 自闭症谱系障碍（ASD）是一种神经发育障碍，分为两个主要的诊断标准- 社会沟通和互动的持续缺陷，以及存在限制性的重复模式， 行为纹状体是基底神经节的主要输入中心， 重复行为在动作选择、运动学习和习惯形成中发挥作用。尽管有明显的联系 纹状体功能和ASD相关的行为改变之间的关系，一般来说，纹状体和基底神经节， 在ASD研究中仍然相对不足。我们实验室和其他实验室最近的工作表明， 在小鼠中ASD风险基因的细胞类型特异性缺失足以增加加速生长的性能。 rotarod任务，一种纹状体依赖性运动学习试验，用作获得性重复行为的代理。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。 连通性。总之，这项工作表明，增强皮质纹状体驱动可能会促进获得固定的 在ASD相关遗传扰动的背景下的运动程序。 在这个提议中，我将检验这样一个假设，即纹状体，特别是皮质纹状体， 在ASD小鼠模型中，可塑性通常会发生改变，这些ASD小鼠模型在一系列风险基因中含有突变。在 此外，我将确定ASD风险基因的突变如何影响纹状体依赖的运动和习惯学习。我 将重点研究三种自闭症小鼠模型，这些小鼠模型中编码一系列蛋白质的ASD风险基因被破坏 类型：Cntnap 2，编码突触粘附分子，Pten，编码磷酸酶， 负调节AKT和mTOR信号传导，以及编码电压门控钠通道的Scn 2a。我 将通过利用行为来确定这些模型中纹状体依赖性行为的潜在改变， 评估被认为依赖于皮质纹状体突触传递的习得性运动行为的测定。我 然后将评估这些突变对多刺投射神经元（SPN）生理特性的影响， 纹状体的主要输出细胞，并试图通过修改 SPN兴奋性。这些实验将增加我们对纹状体病理生理学如何影响 并且可以识别在遗传上共享的突触或电路水平上的会聚点。 各种形式的ASD。这样的结果可能使设计治疗，可以恢复纹状体功能 在ASD的背景下。