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

项目摘要/摘要 雷特综合征是一种毁灭性的儿童神经障碍，剥夺了年轻女孩的运动，语言， 和社交技能。虽然Rett综合征的遗传原因在20年前就被发现了，但准确的 MECP2基因突变导致Rett综合征的机制仍不清楚。这样一个关键的差距 知识阻碍了有效治疗方法的发展。之前的研究已经强调了 MeCP2在大脑多个区域的重要性。然而，MeCP2在协调 尽管运动不协调和共济失调是Rett的显著特征，但小脑仍然未知。 综合症。为了解决这个问题，我研究了小脑中有条件地缺乏MeCP2的小鼠，发现它们 表现出运动缺陷，随着延长训练时间的延长而改善。我用神经解剖学分析，体内的钙 成像和活体电生理学来探索小脑潜在的网络功能障碍。这个 延长训练挽救了运动缺陷的事实增加了神经回路影响的令人兴奋的可能性 由MeCP2引起的功能障碍是可以干预的。我证实了这个假设，证明了 对有症状的MeCP2/雌性(Rett)小鼠进行延长训练，这是一种临床相关的全局MeCP2模型 功能障碍，部分改善了他们的运动障碍。因为Rett综合征的临床病程开始了 随着一段时间的正常发展，我从症状前期开始进行运动训练。至 令我惊讶的是，症状前的训练极大地提高了Rett小鼠的运动能力。我会继续努力 这些令人鼓舞的结果并探索了扩展训练克服空间学习缺陷的能力， 雷特综合征的另一个令人衰弱的特征。这些发现将提供对起源的机械性见解。 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这种疾病的多种症状。这一点的影响 研究具有治疗潜力，作为症状前诊断和早期康复可能是关键 修改Rett综合征的临床方面。

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.