Pharmacological modulation of neuronal activity to treat Rett syndrome

Rett syndrome (RTT) is a neurodevelopmental disorder, representing the most common genetic cause of severe intellectual disability in females. RTT is caused by mutations in the X-linked MECP2 gene. Given its role as master regulator of gene expression, transcriptional maturation is affected in null neurons, as well as the ability to respond to external stimuli. Neuronal activity plays a key role during brain development, thus we tested the possible causative link between immaturity and reduced activity by pharmacologically stimulating in vitro and in vivo Mecp2 null neurons within different time windows of differentiation. To enhance activity, we used a positive AMPA receptor modulator, Ampakine CX546. By treating neurons we ameliorated their transcription and activity, highlighting the contribution of defective mechanisms of development to RTT phenotypes. In vivo the efficacy was tested by evaluating the well-being of mice and by performing motor and cognitive behavioral tests. Although the early time window suggested a prolonged benefic effect on knock-out mice, it was devoid of translational value. Therefore, to validate the possibility that ampakine might represent a safe and efficient approach for the treatment of RTT, we tested different time windows with different ampakines. Obtained results will be presented and future perspective discussed.