Rett syndrome (RTT) is an autism spectrum disorder caused by mosaic expression of mutant copies of the X-linked MECP2 gene in neurons. The study shows that in a mouse model of RTT, activation of MeCP2 expression can reverse neurological symptoms. The Mecp2 gene is essential for neuronal development, and its absence leads to a neurodevelopmental disorder rather than a neurodegenerative one. Using a mouse model, researchers demonstrated that re-expression of MeCP2 can restore normal function and reverse RTT symptoms. They created a mouse model with a conditional Mecp2 gene that could be activated by tamoxifen (TM). Activation of MeCP2 led to the reversal of neurological symptoms in both immature and mature animals. The study also showed that gradual activation of MeCP2, rather than sudden reactivation, was less toxic and more effective in reversing symptoms. In mature female heterozygotes, TM treatment reversed neurological symptoms and obesity. The results suggest that RTT is not strictly a neurodevelopmental disorder, as developmental absence of MeCP2 does not irreversibly damage neurons. The study also showed that long-term potentiation (LTP) deficits in RTT mice were reversed by MeCP2 reactivation. These findings indicate that neurological defects in RTT and related disorders may be reversible. The study provides evidence that late-onset neurological symptoms in mature adult heterozygotes can be reversed by de novo expression of MeCP2. The results suggest that the molecular preconditions for normal MeCP2 activity are preserved in its absence, and that essential MeCP2 target sites in neuronal genomes are encoded by DNA methylation patterns. The study concludes that RTT-like neurological defects due to absence of the Mecp2 gene can be rectified by delayed restoration of that gene. The experiments do not suggest an immediate therapeutic approach to RTT, but they establish the principle of reversibility in a mouse model and raise the possibility that neurological defects seen in this and related human disorders are not irrevocable.Rett syndrome (RTT) is an autism spectrum disorder caused by mosaic expression of mutant copies of the X-linked MECP2 gene in neurons. The study shows that in a mouse model of RTT, activation of MeCP2 expression can reverse neurological symptoms. The Mecp2 gene is essential for neuronal development, and its absence leads to a neurodevelopmental disorder rather than a neurodegenerative one. Using a mouse model, researchers demonstrated that re-expression of MeCP2 can restore normal function and reverse RTT symptoms. They created a mouse model with a conditional Mecp2 gene that could be activated by tamoxifen (TM). Activation of MeCP2 led to the reversal of neurological symptoms in both immature and mature animals. The study also showed that gradual activation of MeCP2, rather than sudden reactivation, was less toxic and more effective in reversing symptoms. In mature female heterozygotes, TM treatment reversed neurological symptoms and obesity. The results suggest that RTT is not strictly a neurodevelopmental disorder, as developmental absence of MeCP2 does not irreversibly damage neurons. The study also showed that long-term potentiation (LTP) deficits in RTT mice were reversed by MeCP2 reactivation. These findings indicate that neurological defects in RTT and related disorders may be reversible. The study provides evidence that late-onset neurological symptoms in mature adult heterozygotes can be reversed by de novo expression of MeCP2. The results suggest that the molecular preconditions for normal MeCP2 activity are preserved in its absence, and that essential MeCP2 target sites in neuronal genomes are encoded by DNA methylation patterns. The study concludes that RTT-like neurological defects due to absence of the Mecp2 gene can be rectified by delayed restoration of that gene. The experiments do not suggest an immediate therapeutic approach to RTT, but they establish the principle of reversibility in a mouse model and raise the possibility that neurological defects seen in this and related human disorders are not irrevocable.