Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.
Nature. 2021 Apr;592(7855):596-600. doi: 10.1038/s41586-021-03369-7. Epub 2021 Mar 24.
Mutations in the X-linked gene MECP2 cause Rett syndrome, a progressive neurological disorder in which children develop normally for the first one or two years of life before experiencing profound motor and cognitive decline. At present there are no effective treatments for Rett syndrome, but we hypothesized that using the period of normal development to strengthen motor and memory skills might confer some benefit. Here we find, using a mouse model of Rett syndrome, that intensive training beginning in the presymptomatic period dramatically improves the performance of specific motor and memory tasks, and significantly delays the onset of symptoms. These benefits are not observed when the training begins after symptom onset. Markers of neuronal activity and chemogenetic manipulation reveal that task-specific neurons that are repeatedly activated during training develop more dendritic arbors and have better neurophysiological responses than those in untrained animals, thereby enhancing their functionality and delaying symptom onset. These results provide a rationale for genetic screening of newborns for Rett syndrome, as presymptomatic intervention might mitigate symptoms or delay their onset. Similar strategies should be studied for other childhood neurological disorders.
X 连锁基因 MECP2 的突变导致雷特综合征，这是一种进行性神经疾病，患儿在生命的头一两年内发育正常，之后会出现严重的运动和认知衰退。目前，雷特综合征尚无有效治疗方法，但我们假设利用正常发育时期来增强运动和记忆技能可能会带来一些益处。在这里，我们通过雷特综合征的小鼠模型发现，从症状前阶段开始的强化训练可显著改善特定运动和记忆任务的表现，并显著延迟症状发作。而当训练从症状出现后开始时，则观察不到这些益处。神经元活动标志物和化学遗传操作表明，在训练过程中反复激活的特定任务神经元比未经训练的动物具有更多的树突分支，并且具有更好的神经生理反应，从而增强了其功能并延迟了症状发作。这些结果为新生儿进行雷特综合征的基因筛查提供了依据，因为症状前干预可能会减轻症状或延迟其发作。其他儿童神经疾病也应该研究类似的策略。
