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Tsc1 Regulation of Purkinje Neuron Firing and Cerebellar Function

Tsc1 对浦肯野神经元放电和小脑功能的调节

基本信息

批准号：
10360002
负责人：
Joseph L. Ransdell
金额：
$ 36.13万
依托单位：
MIAMI UNIVERSITY OXFORD
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：
2022-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10360002
关键词：
Action Potentials Acute Address Affect Alleles Animal Model Animals Attenuated Axon Behavior Behavioral Biophysics Calcium Cerebellar Diseases Cerebellar Nuclei Cerebellum Communication Complex Diagnosis Disease Electrophysiology (science)Exhibits Fire - disasters Functional disorder Genes Genetic Goals Guanosine Triphosphate Phosphohydrolases Impairment Individual Intellectual functioning disability Laboratories Link Measures Mediating Membrane Metabolism Molecular Molecular Genetics Motor Movement Mus Mutation Neurodevelopmental Disorder Neurons Persons Potassium Potassium Channel Property Protein-Serine-Threonine Kinases Regulation Research SLC12A3 gene Seizures Signal Pathway Signal Transduction Social Interaction Sodium Symptoms TSC1 gene TSC1/2 gene Techniques Testing Training Tuberous Sclerosis Universities Work autism spectrum disorder autistic behaviour base behavioral phenotyping cell growth cell type genetic approach graduate student in vivo knock-down loss of function mutation motor deficit motor impairment mouse model nervous system disorder neural circuit novel sodium ion targeted treatment undergraduate student vocalization voltage

项目摘要

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder that affects an estimated 1 in 59 individuals. ASD diagnoses involve a range and often heterogenous assortment of symptoms, which include impaired social interactions, motor coordination, communication ability, and vocalizations, as well as exaggerated repetitive movements. Our understanding, however, of the molecular, cellular, and neural circuit dysfunction that drives ASD-linked behaviors remains unclear. Another neurodevelopmental disorder, tuberous sclerosis, is caused by loss of function mutations in tuberous sclerosis 1 or 2 (Tsc1, Tsc2). Interestingly, >50% of individuals with Tsc are also diagnosed with ASD, making Tsc mutations one of the most prevalent monogenetic causes of ASD. In mice, the selective deletion of one or two Tsc1 alleles selectively in cerebellar Purkinje neurons (Pcp2:Tsc1+/-, Pcp2:Tsc1-/-) results in multiple autistic-like behaviors. With this animal model, we can connect the dysfunction of a single neuronal cell type, Purkinje neurons in the cerebellum, with autistic-like behaviors. Initial studies using Pcp2:Tsc1 mice revealed that Purkinje neurons lacking Tsc1 expression fire at lower rates than wild type Purkinje neurons. In the following aims, we will extend these studies by (1) defining the molecular and biophysical changes that cause reduced firing rates in Pcp2:Tsc1+/- and Pcp2:Tsc1-/- Purkinje neurons, and (2) determine how the reduced firing rates of Pcp2:Tsc1+/- and Pcp2:Tsc1-/- Purkinje neurons affect the in vivo activity of deep cerebellar nuclei neurons, which, in the context of cerebellar circuits, are the downstream targets of Purkinje neurons. These experimental aims will involve training and collaborative research efforts by graduate and undergraduate students at Miami University.

自闭症谱系障碍（ASD）是一种流行的神经发育障碍，影响儿童