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

摘要 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分类- 社会沟通和互动的持续缺陷，以及存在受限、重复的模式 行为。纹状体是基底神经节的主要输入中枢，与临床表现有关。 重复行为在动作选择、运动学习和习惯养成中的作用。尽管有明确的联系 在纹状体功能和ASD相关的行为改变之间，纹状体和基底节一般， 在ASD研究中仍然相对较少被探索。我们实验室和其他实验室最近的研究表明，纹状体 在小鼠中，ASD危险基因的细胞类型特异性缺失足以提高在加速 Rotarod任务，一种纹状体依赖的运动学习测试，用作后天重复行为的替代。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的增加有关 连通性。综上所述，这项工作表明，增强的皮质纹状体驱动力可能促进获得固定的 在自闭症相关遗传扰动的背景下的运动常规。 在这项提议中，我将检验纹状体，特别是皮质纹状体、连接性和突触的假设 在一系列风险基因突变的ASD小鼠模型中，可塑性通常会发生改变。在……里面 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 将重点放在三种自闭症小鼠模型上，以及编码一系列蛋白质的自闭症风险基因的破坏 类型：cntnap2，编码突触黏附分子，Pten，编码磷酸酶， 负调控AKT和mTOR信号，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行为的潜在变化 评估被认为依赖于皮质纹状体突触传递的习得运动行为的分析。我 然后将评估这些突变对棘突投射神经元(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的理解。 到ASD，并可以识别在突触或回路水平上的汇聚点，这些汇聚点在基因上是共享的 各种形式的自闭症。这样的结果可能使设计出能够恢复纹状体功能的疗法成为可能 在ASD的背景下。

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.