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Presymptomatic training mitigates functional deficits in a mouse model of Rett syndrome
Nathan P Achilly1,2,3, Wei Wang1,4, Huda Y Zoghbi5,6,7,8,9,10,11
1Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
Insights
Early intervention through intensive training can significantly improve motor and memory skills in Rett syndrome mouse models. This presymptomatic training delays symptom onset, unlike training after symptoms appear.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Rett syndrome is a severe neurodevelopmental disorder caused by mutations in the MECP2 gene.
- Patients experience normal early development followed by progressive motor and cognitive decline.
- Currently, no effective treatments exist for Rett syndrome.
Purpose of the Study:
- To investigate if intensive training during the presymptomatic period can mitigate symptoms of Rett syndrome.
- To explore the neurobiological mechanisms underlying the effects of early intervention.
Main Methods:
- Utilized a mouse model of Rett syndrome.
- Implemented intensive motor and memory training during the presymptomatic phase.
- Assessed behavioral performance, neuronal activity markers, and neurophysiological responses.
Main Results:
- Presymptomatic intensive training significantly improved motor and memory task performance.
- Training delayed the onset of Rett syndrome symptoms.
- Post-symptom onset training did not yield similar benefits.
- Training enhanced neuronal function, including dendritic arborization and neurophysiological responses.
Conclusions:
- Early, presymptomatic intervention through targeted training can be beneficial for Rett syndrome.
- Neuronal plasticity in response to training plays a key role in delaying symptom onset.
- Findings support newborn screening and early intervention strategies for Rett syndrome and similar disorders.
Abstract:
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 decline1-3. 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.
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