Driving Behavioral Rescue and Molecular Modulation through Neuronal Stimulation in Rett Syndrome

Rett syndrome (RTT) 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; as a consequence, patients manifest critical motor and cognitive disfunction along with a spectrum of respiratory and cardiac abnormalities. Since a feedforward cycle between gene transcription and neuronal maturation has been postulated, we hypothesized that impaired transcription in RTT disrupts this loop and thereby tested the therapeutic value of stimulating neuronal activity through a clinical grade positive allosteric modulator of AMPA receptors. Beneficial effects were initially proved in mouse context. In vitro, the drug rescued multiple RTT-related phenotypes exhibited by Mecp2 knockout primary neurons. Therapeutic efficacy was then assessed in vivo in RTT mice. We found that a short, early treatment administered during the peak of brain plasticity induces robust and long-lasting effects, delaying disease progression and rescuing both motor performance and spatial memory. Benefits were prolonged by extending the treatment with an intermittent regimen of administration, and confirmed by ex vivo molecular and electrophysiological analyses carried out starting from the prefrontal cortex of treated mice. As a further step toward the bedside, we are currently assessing the efficacy of Ampakine in RTT human neurons. Overall, our findings emphasize the importance of early intervention to restore neuronal circuits and suggest a new frontier in Rett syndrome care.