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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) 是一种常见的神经发育障碍，影响估计每 59 个人中就有 1 人。自闭症谱系障碍 (ASD) 诊断涉及范围广泛且经常不同种类的症状，包括社交互动受损，运动协调、沟通能力和发声能力，以及夸张的能力重复的动作。然而，我们对分子、细胞和驱动 ASD 相关行为的神经回路功能障碍仍不清楚。其他神经发育障碍，结节性硬化症，是由功能丧失引起的结节性硬化症 1 或 2（Tsc1、Tsc2）突变。有趣的是，>50% 的人患有 Tsc 的人也被诊断患有自闭症谱系障碍 (ASD)，这使得 Tsc 突变成为最常见的突变之一 ASD 的单基因原因。在小鼠中，选择性删除一个或两个 Tsc1 等位基因选择性地作用于小脑浦肯野神经元 (Pcp2:Tsc1+/-, Pcp2:Tsc1-/-) 导致多个类似自闭症的行为。通过这个动物模型，我们可以将动物的功能障碍联系起来单一神经元细胞类型，小脑中的浦肯野神经元，具有自闭症样行为。使用 Pcp2:Tsc1 小鼠的初步研究表明，浦肯野神经元缺乏 Tsc1 表达激发率低于野生型浦肯野神经元。在下文中目标，我们将通过（1）定义分子和生物物理来扩展这些研究导致 Pcp2:Tsc1+/- 和 Pcp2:Tsc1-/- Purkinje 放电率降低的变化 (2) 确定 Pcp2:Tsc1+/- 和 Pcp2:Tsc1-/- 浦肯野神经元的放电率降低如何影响小脑深核神经元的体内活动，这在小脑回路的背景是浦肯野神经元的下游目标。这些实验目标将涉及培训和合作研究工作迈阿密大学的研究生和本科生。