Cerebellar granule cell dysfunction in Shank3 mutant mice

项目总结/摘要 自闭症谱系障碍（ASD）是一种复杂的神经系统疾病，与广泛的 基因突变和环境因素。虽然确定ASD的神经基础一直是一个 遗传学和神经科学领域的主要焦点，目前尚不清楚哪些大脑区域和细胞类型可能是 功能异常导致ASD。小脑，一个通常被认为与大脑活动有关的区域， 运动协调和控制，由于其在ASD中的潜在作用而受到相当大的关注， 将ASD诊断与小脑解剖、功能和 运动或前庭行为/功能。与此同时，小脑参与运动系统以外的回路， 为小脑提供了一个影响非运动行为和过程的基底，为 适当的小脑功能在一系列神经过程中的重要性。在小脑中，最初的 所有进入小脑皮质的感觉运动信息的整合都是由 颗粒细胞形态简单且密度极高。这些颗粒细胞也表达许多 高风险ASD相关基因，特别是那些参与突触传递和发育的基因。不过小 已知许多ASD相关基因在小脑，特别是颗粒细胞中的作用和重要性。 目前还不清楚小脑颗粒细胞功能和连接的哪些方面可能对塑造重要 某些非运动（和运动）行为。为了弥补这一知识差距，在目标1和2中，我们建议确定 ASD连锁基因决定小脑颗粒细胞突触相互作用特性的程度 和皮层回路动态变化的关系在目标3中，我们将确定一个特定的ASD连锁基因是如何在小脑中表达的。 颗粒细胞影响运动和非运动域的行为表型。拟议的结果 这项工作将是确定与ASD相关的基因/蛋白质与特定突触之间的机制联系的关键。 小脑异常

PROJECT SUMMARY/ABSTRACT Autism spectrum disorder (ASD) is a complex neurological disorder associated with a broad collection of genetic mutations and environmental factors. While identifying the neural underpinnings of ASD has been a major focus in the field of genetics and neuroscience, it is not clear which brain region (s) and cell types may be functioning abnormally to give rise to ASD. The cerebellum, a brain region typically considered to be involved in motor coordination and control, has received considerable attention for its potential role in ASD, with a growing body of clinical evidence correlating ASD diagnoses with abnormalities in cerebellar anatomy, function, and motor or vestibular behaviors/functions. In parallel, cerebellar involvement in circuits outside of the motor system provides a substrate for the cerebellum to influence non-motor behaviors and processes, setting the stage for the importance of appropriate cerebellar function in a host of neural processes. Within the cerebellum, the initial integration of all incoming sensorimotor information entering the cerebellar cortex is carried out by the morphologically simple and extremely dense population of granule cells. These granule cells also express many high risk ASD-linked genes, especially those involved in synaptic transmission and development. However, little is known about the role and importance of many ASD-linked genes in the cerebellum, especially in granule cells. It is also not clear what aspects of cerebellar granule cell function and connectivity may be important for shaping certain non-motor (and motor) behaviors. To address this knowledge gap, in aims 1 and 2 we propose to identify the degree to which an ASD-linked gene determines properties of cerebellar granule cell synaptic interactions and cortical circuitry dynamics over time. In Aim 3, we will identify how a particular ASD-linked gene in cerebellar granule cells influence behavioral phenotype across motor and non-motor domains. Results from the proposed work will be key in identifying a mechanistic link between a gene/protein linked to ASD and specific synaptic abnormalities in the cerebellum.