Mechanisms of Motor Skill Learning in the Fragile X Mouse Model

描述（由申请人提供）：脆性X综合征（FXS）是智力残疾最常见的遗传形式。已发现患有FXS的儿童在学习熟练肢体运动的表现方面存在发育障碍。运动技能学习被认为需要初级运动皮层（M1）中的突触可塑性。为了更好地理解神经元通信如何随着运动学习而改变，有必要确定学习是否可以诱导突触的数量，形态，功效和分子组成的变化。FXS是由编码脆性X智力低下蛋白（FMRP）的FMR1基因沉默突变引起的。在这里，我们将使用fmr1基因敲除小鼠，一种FXS的小鼠模型，来研究初级运动皮层的学习机制。我们的目标是了解如何fmr1有助于调节运动皮层的突触可塑性，从而阐明在fmr1 KO运动技能学习缺陷的机制。我们将结合联合收割机的行为，电生理，药理学，双光子成像和分子的方法来表征的变化，发生在突触在M1的fmr1基因敲除小鼠学习一种新的运动技能。这项工作有望为开发FXS和其他神经发育障碍（如自闭症）的疗法提供重要知识，这是NIH的一项使命。! 公共卫生相关性：脆性X综合征（FXS）和自闭症患者在学习熟练肢体运动的表现方面存在发育障碍。因此，确定正常和发育异常大脑中控制运动学习的细胞机制至关重要。在这里，我们将在FXS小鼠模型中研究运动学习的机制。这将有助于确定FXS运动技能缺陷的神经生物学基础，并有助于确定治疗靶点。

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common inherited form of an intellectual disability. Children with FXS have been found to have a developmental impairment in the performance of learned skilled limb movements. Motor skill learning is thought to require synaptic plasticity in the primary motor cortex (M1). To better understand how neuronal communication changes with motor learning, it is necessary to determine if learning can induce changes in number, morphology, efficacy, and molecular composition of synapses. FXS results from mutation that causes silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP). Here we will use the fmr1 KO mouse, a murine model for FXS, to study the mechanisms of learning in the primary motor cortex. Our goal is to understand how fmr1 contributes to regulation of synaptic plasticity in the motor cortex and thus elucidate the mechanisms of motor skill learning deficits in the fmr1 KO. We will combine behavioral, electrophysiological, pharmacological, 2-photon imaging and molecular approaches to characterize the changes that occur at synapses in M1 following the learning of a new motor skill in the fmr1 KO mouse. This work is expected to provide important knowledge to develop therapies for FXS and other neurodevelopmental disorders such as autism, a mission of the NIH. ! PUBLIC HEALTH RELEVANCE: Fragile X syndrome (FXS) and autism patients have a developmental impairment in the performance of learned skilled limb movements. It is therefore critical to determine the cellular mechanisms that govern motor learning in normal and developmentally abnormal brain. Here we will study the mechanism of motor learning in a mouse model of FXS. This will help to determine the neurobiological basis of the motor skill deficits in FXS and help identify therapeutic targets.