This study shows for the first time that JNK kinase in the brain is activated both in the absence (Mecp2y/−) and in the female mosaicism expression of Mecp2 mutation and wild type allele (Mecp2+/− Jae mice) and the specific inhibition of JNK reverses RTT signs/symptoms in both mouse models. This evidence concerns the gene MAPK8 and Rett syndrome.