Unveiling the effect of early glutamatergic stimulation for Rett syndrome treatment

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder associated with MECP2 mutations and is the primary cause of severe intellectual disability in girls worldwide. MeCP2 acts as a master regulator of gene expression, and its deficiency results in various molecular abnormalities, including synaptic dysfunction and a subsequent decline in neuronal connectivity and plasticity. Phenotypically, patients undergo canonical development up to six months of age, but within the second year of life a regression phase occurs, leading to the loss of their motor and communication skills, accompanied by stereotypic movements, seizure, breathing irregularities and autistic-like features. Nowadays there is no cure for RTT, apart from Trofinetide, an FDA-approved drug introduced in 2023 that provides symptomatic relief but comes with certain drawbacks. As a result, ongoing research remains a pressing social necessity. Given the positive reciprocal relationship between gene transcription and neuronal maturation, we sought to enhance this process by stimulating AMPA receptors using a clinically approved ampakine to restore neuronal activity. Initial in vitro studies conducted on Mecp2 knockout primary neurons demonstrated the drug’s beneficial effects. Specifically, treated RTT neurons displayed an increased presence of synaptic markers and more functionally active synapses compared to untreated neurons. Moreover, drug-treated neurons exhibited greater electrical activity than their untreated counterparts. The therapeutic potential was further evaluated in vivo using Mecp2 KO mice, with treatment administered at different developmental stages. While early and short-term intervention significantly improved Rett phenotypes, delayed treatment, aimed to be more translational being administered when the disease starts to manifest, was ineffective in alleviating pathological symptoms. However, extending the treatment through an early intermittent regimen successfully restored motor and cognitive improvements in both male and female mice. The molecular effects of these treatments are currently being explored using an advanced proteomic approach. Overall, our findings highlight the critical role of the glutamatergic system in Rett syndrome and underscore the importance of early therapeutic intervention to restore neuronal networks, paving the way for a novel approach to Rett syndrome treatment.