Understanding the role of MeCP2 in the cerebellum and the therapeutic potential of extended training in Rett syndrome

项目概要/摘要 雷特综合征是一种毁灭性的儿童神经系统疾病，它剥夺了年轻女孩的运动，语言， 和社交能力。虽然Rett综合征的遗传原因在二十年前就被发现了，但确切的原因是， MECP2突变导致Rett综合征的机制仍然是难以捉摸的。如此关键的差距， 知识阻碍了有效治疗的发展。以前的研究强调， MeCP2在许多脑区的重要性。然而，MeCP2在协调细胞功能中的作用是不确定的。 小脑仍然未知，尽管运动不协调和共济失调是Rett的突出特征， 综合征为了解决这个问题，我研究了小脑中条件性缺乏Mecp 2的小鼠，发现它们 表现出运动缺陷，经过长期训练后有所改善。我用神经解剖学分析，体内钙 成像和体内电生理学来探索小脑中潜在的网络功能障碍。的 事实上，延长训练挽救了运动缺陷提出了令人兴奋的可能性，神经回路影响了 由MeCP2功能障碍引起的可接受干预。我证实了这个假设， 在有症状的Mecp2 +/-雌性（Rett）小鼠中进行延长训练，这是一种临床相关的整体MeCP2模型 功能障碍，部分改善他们的运动障碍。因为雷特综合征的临床过程始于 在正常发育的一段时间内，我从症状前开始进行运动训练。到 令人惊讶的是，症状前训练显著改善了Rett小鼠的运动表现。我将继续 这些令人鼓舞的结果，并探索扩展训练的能力，以克服空间学习的缺陷， 雷特综合征的另一个特征这些发现将为我们提供关于 运动不协调和共济失调困扰着Rett综合征患者，并提高了兴奋性 延长训练可能会改善疾病的多种症状。这件事的影响是 有治疗潜力的研究，作为症状前诊断和早期康复可能是关键， 改变Rett综合征的临床表现。

PROJECT SUMMARY/ABSTRACT Rett syndrome is a devastating childhood neurological disorder that robs young girls of their motor, language, and social skills. Although the genetic cause of Rett syndrome was discovered two decades ago, the precise mechanism by which mutations in MECP2 cause Rett syndrome has remained elusive. Such a critical gap in knowledge has hindered the development of effective treatments. Previous studies have highlighted the importance of MeCP2 in many brain regions. However, the role of MeCP2 in orchestrating the functions of the cerebellum remains unknown, despite motor incoordination and ataxia being prominent features in Rett syndrome. To address this, I studied mice conditionally lacking Mecp2 in the cerebellum and found that they displayed motor defects that improved with extended training. I used neuroanatomical analysis, in vivo calcium imaging, and in vivo electrophysiology to explore the underlying network dysfunction in the cerebellum. The fact that extended training rescued the motor defects raised the exciting possibility that neural circuits affected by MeCP2 dysfunction are amenable to intervention. I validated this hypothesis by demonstrating that extended training in symptomatic Mecp2+/- female (Rett) mice, a clinically relevant model of global MeCP2 dysfunction, partially ameliorated their motor impairments. Because the clinical course of Rett syndrome starts with a period of normal development, I performed motor training beginning in the pre-symptomatic period. To my surprise, pre-symptomatic training dramatically improved the motor performance of Rett mice. I will build on these encouraging results and explore the ability of extended training to overcome defects in spatial learning, another debilitating feature of Rett syndrome. These discoveries will provide mechanistic insights into the origin of the motor incoordination and ataxia that plagues patients with Rett syndrome, and raise the exciting possibility that extended training might improve multiple symptoms of the disease. The implications of this study have therapeutic potential as pre-symptomatic diagnosis and early rehabilitation may be the key to modifying clinical aspects of Rett syndrome.