Pharmacological modulation of neuronal activity for the treatment of Rett syndrome

Mutations in the MECP2 gene cause Rett syndrome (RTT), a severe neurodevelopmental disorder that typically affects 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, a positive modulator of AMPA receptor, we ameliorated null neurons transcription, morphology, and activity, highlighting the contribution of defective mechanisms of development to typical RTT phenotypes. Preliminary results suggested a positive result of an early treatment also in vivo. Although the selected time window of treatment suggested a prolonged benefic effect on Mecp2 null mice, it was devoid of translational value. We thus decided to test in vivo later time points. To identify the best therapeutic window for intervention, we selected two pre-symptomatic (P3-P9 and P15-21) time points, an early symptomatic (P28-34) and a late symptomatic (P55-61) phase. First results were collected administrating two different ampakines at P28-P34. The efficacy of the treatment was tested by evaluating the lifespan, the phenotypic score commonly used for RTT mice, and performing some behavioral tests at different time points.