Tsc1 Regulation of Purkinje Neuron Firing and Cerebellar Function

自闭症谱系障碍（ASD）是一种普遍的神经发育障碍， 估计每59个人中就有一个。ASD诊断涉及一个范围，通常 各种各样的症状，包括社会交往障碍， 运动协调，沟通能力和发声，以及夸张的 重复的动作。然而，我们对分子、细胞和 导致自闭症相关行为的神经回路功能障碍仍不清楚。另一 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（Tsc 1，Tsc 2）突变。有趣的是，超过50%的人 患有Tsc的人也被诊断患有ASD，这使得Tsc突变成为最普遍的突变之一。 ASD的单基因原因。在小鼠中，选择性缺失一个或两个Tsc 1等位基因， 选择性地在小脑浦肯野神经元（Pcp2：Tsc 1 +/-，Pcp2：Tsc 1-/-）中产生多个 类似自闭症的行为有了这个动物模型，我们可以把一个 单神经元细胞型，小脑中的浦肯野神经元，具有自闭症样 行为。使用Pcp2：Tsc1小鼠的初步研究显示，浦肯野神经元缺乏 Tsc1表达火率低于野生型浦肯野神经元。在以下 目的，我们将通过以下方式扩展这些研究：（1）定义分子和生物物理 导致Pcp2：Tsc1 +/-和Pcp2：Tsc1-/-浦肯野细胞放电率降低的变化 （2）确定Pcp2：Tsc 1 +/-和Pcp2：Tsc 1-/-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性， 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。

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.