The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes

utations in the MECP2 are causative of Rett syndrome, a severe neurodevelopmental disorder, typically affecting females. Early developmental defects have been reported, but their contribution to the pathogenesis is still not understood. In line with the role of Mecp2 as a master regulator of gene expression, transcriptional maturation is affected in null samples both in vivo and in vitro, as well as the ability of null neurons to respond to external stimuli. We tested the possible causative link between immaturity and reduced neuronal activity by pharmacologically stimulating null neurons within early time windows of differentiation. By treating NPCs derived neurons with Ampakine CX546, we were able to ameliorate Mecp2 null neurons transcription, morphology, and activity, thus highlighting the contribution of defective mechanisms of development to the phenotypes typically displayed by RTT models. Moreover, these beneficial effects persist long after the end of the treatment both in vitro and in vivo.