Targeting neuronal circuits as a new frontier in Rett syndrome treatment

Rett syndrome is an X-linked MECP2-related neurodevelopmental disorder and the leading cause of severe intellectual disability in girls worldwide. MeCP2 functions as a master regulator of gene expression, and its deficiency leads to numerous pathological features, including synaptic alterations and a consequent reduction in neuronal connectivity and plasticity. Since a feedforward cycle exists between gene transcription and neuronal maturation, by stimulating AMPA receptors we aimed to enhance it, thus restoring neuronal activity, through a clinical grade ampakine. Beneficial effects were initially proved in vitro, in Mecp2 knockout primary neurons. Indeed, drug-treated RTT neurons exhibited increased number of synaptic markers along with more active synapses compared to untreated neurons. Therapeutic efficacy was then assessed in vivo in Mecp2 KO mice. Animals were treated at different time windows. While a short and early intervention showed a strong ability to ameliorate RTT phenotype, a delay treatment failed to improve pathological conditions. However, beneficial behavioral effects were restored by prolonging the administration through an intermittent treatment regimen. Molecular consequences of the selected treatments are currently under investigation through a novel proteomic approach. Overall, our findings emphasize the importance of early intervention to restore neuronal circuits and suggest a new frontier in Rett syndrome care.