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) 是一种神经发育障碍，按两个主要诊断标准进行分类 - 社会沟通和互动持续存在缺陷，并且存在受限的、重复的模式 行为。纹状体是基底神经节的主要输入中心，与 考虑到重复行为在动作选择、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 ASD 相关行为改变、纹状体和基底神经节之间的关系， 自闭症谱系障碍（ASD）研究中的探索相对较少。我们实验室和其他人最近的工作表明，纹状体 小鼠中 ASD 风险基因的细胞类型特异性删除足以提高加速性能 旋转任务，一种依赖于纹状体的运动学习测定，用作获得性重复行为的代理。我们 进一步表明，这种运动学习的增强与皮质纹状体兴奋性的增加有关 连接性。这项工作表明，增强的皮质纹状体驱动力可能会促进固定能力的获得。 自闭症谱系障碍（ASD）相关遗传扰动背景下的运动习惯。 在这个提案中，我将检验纹状体，特别是皮质纹状体，连接性和突触的假设 在一系列风险基因发生突变的 ASD 小鼠模型中，可塑性通常会发生改变。在 此外，我将确定 ASD 风险基因的突变如何影响纹状体依赖性运动和习惯学习。我 将重点研究三种自闭症小鼠模型，这些模型破坏了编码一系列蛋白质的自闭症风险基因 类型：Cntnap2，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 Scn2a。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 评估习得运动行为的分析被认为依赖于皮质纹状体突触传递。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，并尝试通过修改来挽救习惯性运动行为的改变 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 可以识别自闭症谱系障碍（ASD），并可以识别跨基因共享的突触或电路水平的收敛点 多种形式的 ASD。这样的结果可能有助于设计能够恢复纹状体功能的疗法 在 ASD 的背景下。