Tsc1 Regulation of Purkinje Neuron Firing and Cerebellar Function

自闭症谱系障碍(ASD)是一种普遍存在的神经发育障碍，影响 据估计，每59人中就有1人。ASD的诊断涉及范围广泛，而且通常 各种不同的症状，包括社交互动障碍， 动作协调，沟通能力，发声，以及夸张 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。另一个 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)的突变。有趣的是，50%的人 患有TSC的人也被诊断为ASD，使TSC突变成为最常见的 ASD的单基因致病因素。在小鼠中，一个或两个TSC1等位基因的选择性缺失 选择性地在小脑浦肯野神经元(Pcp2：Tsc1+/-，Pcp2：Tsc1-/-)导致多个 自闭症样行为。有了这个动物模型，我们可以将 单神经元细胞类型，小脑内的浦肯野神经元，伴有自闭症样 行为。使用Pcp2：TSC1小鼠的初步研究表明，浦肯野神经元缺乏 与野生型浦肯野神经元相比，TSC1的表达频率较低。在以下内容中 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放电频率降低的变化 以及(2)确定Pcp2：Tsc1+/-和Pcp2：Tsc1-/-Purkinje神经元的放电频率降低如何影响小脑深部核神经元的活体活动，在 小脑回路的背景是浦肯野神经元的下游靶点。 这些实验目标将包括培训和合作研究工作，由 迈阿密大学的研究生和本科生。

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.