Cerebellar granule cell dysfunction in Shank3 mutant mice

Shank3突变小鼠的小脑颗粒细胞功能障碍

• 批准号: 10424622
• 负责人: Ben D Richardson
• 金额: $ 36.88万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-23 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10424622
• 关键词: Address; Adult; Affect; Anatomy; Animal Model; Animals; Anxiety; Area; Attention; Behavior; Behavioral; Birth; Brain; Brain region; Cell Nucleus; Cell physiology; Cellular Morphology; Cerebellar Cortex; Cerebellar Diseases; Cerebellum; Child; Clinical; Clinical Data; Cognitive; Collection; Complex; Corpus striatum structure; DNA Sequence Alteration; Data; Development; Diagnosis; Emotional; Environmental Risk Factor; Excision; Face; Foundations; Functional disorder; Gene Proteins; Genes; Genetic; Genomics; Glutamate Receptor; Glutamates; Goals; Human; Incidence; Knowledge; Link; Memory; Molecular; Morphology; Motor; Motor Pathways; Mus; Mutant Strains Mice; Mutation; N-Methyl-D-Aspartate Receptors; Nervous system structure; Neurobiology; Neurodevelopmental Disorder; Neurons; Neurosciences; Output; Play; Population; Prevention; Preventive treatment; Process; Property; Purkinje Cells; Rewards; Role; Sensory; Shapes; Signal Transduction; Site; Slice; Social Behavior; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Syndrome; System; Time; United States; Variant; Work; autism spectrum disorder; base; behavior influence; behavioral phenotyping; brain shape; cell motility; cell type; glutamatergic signaling; granule cell; high risk; link protein; motor behavior; motor deficit; negative affect; nervous system disorder; postnatal; postnatal development; postsynaptic; receptor density; relating to nervous system; response; restorative treatment; social; spatiotemporal; transmission process; treatment strategy

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.

项目摘要/摘要 自闭症谱系障碍（ASD）是一种复杂的神经系统障碍 基因突变和环境因素。在确定ASD的神经基础的同时， 在遗传学和神经科学领域的主要重点，尚不清楚哪个脑区域和细胞类型可能是 异常发挥作用，引起ASD。小脑，通常被认为参与的大脑区域 运动协调和控制，因其在ASD中的潜在作用而受到了极大的关注，并且不断增长 临床证据的体系与小脑解剖学，功能和功能异常的ASD诊断相关 运动或前庭行为/功能。同时，小脑参与电机系统外的电路 为小脑提供了影响非运动行为和过程的底物，为 适当的小脑功能在许多神经过程中的重要性。在小脑内，初始 进入小脑皮层的所有传入的感觉运动信息的整合是由 形态学上简单且非常密集的颗粒细胞。这些颗粒细胞也表达了许多 高风险与ASD相关的基因，尤其是参与突触传播和发育的基因。但是，很少 知道许多ASD连接基因在小脑中，尤其是在颗粒细胞中的作用和重要性。 还不清楚小脑颗粒细胞功能的哪些方面和连通性对于塑造可能很重要 某些非运动（和运动）行为。为了解决这一知识差距，在目标1和2中，我们建议确定 ASD连接基因确定小脑颗粒细胞突触相互作用的特性的程度 随着时间的推移，皮质电路动力学。在AIM 3中，我们将确定小脑中特定的ASD连接基因如何 颗粒细胞会影响跨电动机和非运动结构域的行为表型。提议的结果 工作将是识别与ASD相关的基因/蛋白质与特定突触的基因/蛋白质之间的机械联系的关键 小脑异常。