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）是最常见的遗传形式的智力残疾。患有FXS的儿童在习得的熟练肢体运动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）的突触可塑性。为了更好地理解神经元通讯是如何随着运动学习而改变的，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是由一种突变导致编码脆性X智力迟钝蛋白（FMRP）的FMR1基因沉默而导致的。在这里，我们将使用FXS的小鼠模型fmr1 KO小鼠来研究初级运动皮层的学习机制。我们的目标是了解fmr1如何参与运动皮层突触可塑性的调节，从而阐明fmr1 KO中运动技能学习缺陷的机制。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表征fmr1 KO小鼠学习新运动技能后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（如自闭症）的治疗方法提供重要知识，这是NIH的一项使命。！

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. !