Mechanisms of Motor Skill Learning in the Fragile X Mouse Model

描述(申请人提供)：脆性X综合征(FXS)是最常见的遗传性智力残疾形式。患有FXS的儿童被发现在习得的熟练肢体运动的表现方面存在发育障碍。运动技能的学习被认为需要初级运动皮质(M1)的突触可塑性。为了更好地了解神经元通信是如何随着运动学习而变化的，有必要确定学习是否可以导致突触的数量、形态、有效性和分子组成的变化。FXS是由突变导致编码脆性X智力低下蛋白(FMRP)的FMR1基因沉默引起的。在这里，我们将使用FXS的小鼠模型fmr1KO小鼠来研究初级运动皮质的学习机制。我们的目标是了解fmr1如何参与运动皮质突触可塑性的调节，从而阐明fmr1 KO中运动技能学习障碍的机制。我们将结合行为学、电生理学、药理学、双光子成像和分子方法来描述在fmr1KO小鼠学习新的运动技能后，M1突触发生的变化。这项工作有望为开发FXS和其他神经发育障碍的治疗方法提供重要知识，如NIH的任务自闭症。

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.