Targeting early network dysfunction in Rett syndrome through AMPA-receptor modulation

Mutations in the MECP2 gene cause Rett syndrome (RTT), the leading genetic cause of severe intellectual disability in girls. Although Trofinetide has recently been approved by the FDA as the first treatment for RTT, there remains a strong need for disease-modifying therapies. RTT is traditionally considered a neurodevelopmental disorder with delayed symptom onset; however, increasing evidence shows that MeCP2 deficiency disrupts brain development from very early stages. Accordingly, we previously demonstrated that early maturing Mecp2 null neurons show widespread transcriptional alterations, reduced activity, and impaired morphology¹. Notably, these features appear interconnected in a feed-forward loop, where neuronal activity promotes transcriptional and structural maturation, further enhancing network development. We hypothesize that impaired transcription in RTT neurons disrupts this loop, thereby contributing to the immature state of RTT neuronal networks. Supporting this hypothesis, we recently showed that early enhancement of activity in cultured Mecp2 null neurons rescues multiple RTT-related phenotypes². Building on these findings, we tested the therapeutic potential of a clinical-grade positive allosteric modulator (PAM) of AMPA receptors in Mecp2 deficient 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 perfomance and spatial memory. Furthermore, repeated treatment cycles led to enhanced benefits in both hemizygous male and heterozygous female RTT mouse models, reinforcing the therapeutic promise of this strategy. In this presentation, we will present these findings and discuss the molecular mechanisms restored by treatment, offering new insights into early intervention strategies for RTT.