PDF(Pubmed)
Abstract：
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a rare neurodevelopmental disease caused by mutations in the X-linked CDKL5 gene. CDD is characterized by a broad spectrum of clinical manifestations, including early-onset refractory epileptic seizures, intellectual disability, hypotonia, visual disturbances, and autism-like features. The Cdkl5 knockout (KO) mouse recapitulates several features of CDD, including autistic-like behavior, impaired learning and memory, and motor stereotypies. These behavioral alterations are accompanied by diminished neuronal maturation and survival, reduced dendritic branching and spine maturation, and marked microglia activation. There is currently no cure or effective treatment to ameliorate the symptoms of the disease. Aerobic exercise is known to exert multiple beneficial effects in the brain, not only by increasing neurogenesis, but also by improving motor and cognitive tasks. To date, no studies have analyzed the effect of physical exercise on the phenotype of a CDD mouse model. In view of the positive effects of voluntary running on the brain of mouse models of various human neurodevelopmental disorders, we sought to determine whether voluntary daily running, sustained over a month, could improve brain development and behavioral defects in Cdkl5 KO mice. Our study showed that long-term voluntary running improved the hyperlocomotion and impulsivity behaviors and memory performance of Cdkl5 KO mice. This is correlated with increased hippocampal neurogenesis, neuronal survival, spine maturation, and inhibition of microglia activation. These behavioral and structural improvements were associated with increased BDNF levels. Given the positive effects of BDNF on brain development and function, the present findings support the positive benefits of exercise as an adjuvant therapy for CDD.
摘要：
细胞周期蛋白依赖性激酶样5（CDKL5）缺乏症（CDD）是一种由X连锁CDKL5基因突变引起的罕见神经发育疾病。CDD的特点是广泛的临床表现，包括早发性难治性癫痫发作，智力残疾,低张力,视觉障碍,和类似自闭症的特征。Cdkl5敲除（KO）小鼠概括了CDD的几个特征，包括自闭症样行为，学习和记忆受损，和运动刻板印象。这些行为改变伴随着神经元成熟和存活的减少，减少树突分支和脊柱成熟，和显著的小胶质细胞激活。目前没有治愈或有效的治疗来改善该疾病的症状。众所周知，有氧运动可以在大脑中发挥多种有益作用，不仅通过增加神经发生，还可以通过改善运动和认知任务。迄今为止,没有研究分析体育锻炼对CDD小鼠模型表型的影响.鉴于自愿跑步对各种人类神经发育障碍小鼠模型大脑的积极影响，我们试图确定是否自愿每天跑步，持续了一个多月，可以改善Cdkl5KO小鼠的大脑发育和行为缺陷。我们的研究表明，长期自愿跑步改善了Cdkl5KO小鼠的过度运动和冲动行为以及记忆表现。这与海马神经发生增加有关，神经元存活，脊柱成熟,和抑制小胶质细胞的激活。这些行为和结构的改善与BDNF水平的增加有关。鉴于BDNF对大脑发育和功能的积极影响，本研究结果支持运动作为CDD辅助治疗的积极益处.
