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Cerebellar granule cell dysfunction in Shank3 mutant mice

Shank3突变小鼠的小脑颗粒细胞功能障碍

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘