Pharmacological modulation of neuronal activity for the treatment of Rett syndrome

Rett syndrome (RTT) is a neurodevelopmental disorder, representing the most common genetic cause of severe intellectual disability in females. More than 95% of classical RTT cases are caused by mutations in the X-linked MECP2 gene, and in line with its role as a master regulator of gene expression, null neurons display widespread transcriptional changes, reduced activity, and defective morphology. These elements are linked in a feed-forward cycle where neuronal activity drives transcriptional and morphological changes that increase network maturity. Neuronal activity plays a key role during brain development, thus any variation from physiological ranges leads to severe consequences. We tested the possible causative link between immaturity and reduced neuronal activity by pharmacologically stimulating in vitro and in vivo Mecp2 null neurons within different time windows of differentiation. Methods: To enhance activity and rescue maturation in vitro, we used Ampakine CX546, a positive AMPA receptor modulator. The efficacy of an early treatment with CX546 in vivo was tested by evaluating the general well-being of mice, and by performing motor and cognitive behavioral tests. Moreover, we tested the value of a prolonged treatment in which animals were injected mice every other week. Results: By treating cortical neurons with CX546 we ameliorated null neurons transcription and activity, highlighting the contribution of defective mechanisms of development to typical RTT phenotypes. Although the early time window of treatment in vivo suggested a prolonged benefic effect on knock-out mice, it was devoid of translational value. We thus tested later timepoints and different Ampakines. Conclusions: Our results support the value of an early therapeutic approach acting on neuronal activity as a strategy for RTT therapy. More studies are needed to pinpoint the correct time window and to identify the molecular pathways involved in any observed benefits.