Exercise reduces MeCP2 binding to methylated DNA at BDNF promoter IV, promoting BDNF expression. MeCP2 phosphorylation (S421) is required to dissociate it from the promoter, allowing transcription of BDNF, which is crucial for synaptic plasticity and memory. In Mecp2 mutant mice (Rett syndrome model), exercise restores BDNF levels and improves cognitive deficits. This evidence concerns the gene MECP2 and atypical Rett syndrome.