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

• 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
• 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

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。

项目成果

A Reinterpretation of the Relationship Between Persistent and Resurgent Sodium Currents.

持续性钠流与复苏性钠流之间关系的重新解释。

• 发表时间: 2023-12-22
• 作者: Brown, Samuel P;Lawson, Ryan J;Moreno, Jonathan D;Ransdell, Joseph L
• 通讯作者: Ransdell, Joseph L