Introduction: Rett syndrome (RTT) is a rare neurodevelopmental disorder caused in 95% of cases by mutations in the X-linked methyl CpG-binding protein 2 (MeCP2) gene. Although apparently normal at birth, RTT patients manifest a regression phase between 6-18 months of age characterized by loss of speech, impaired motor functions, seizures and intellectual disabilities. Clinical and animal studies suggested that metabolic pathways might be affected and contribute to RTT pathophysiology. Autophagy is a catabolic process involved in the degradation of cellar debris and recently found to regulate all steps of neurodevelopment, including neurite overgrowth and differentiation. Interestingly, autophagy was found altered in fibroblasts of RTT patients. In this project, we aim at performing a pharmacological screening of autophagy modulators in a cellular model of RTT and evaluate whether autophagy enhancement could recover neuronal defects. Methods: Primary cortical neurons derived from WT and Mecp2-null embryos (E15.5) were treated with selected drugs (DIV12 to DIV14) and tested for the autophagic markers LC3B-II and p62 by western blot. Then, morphological and functional deficits associated with Mecp2 deficiency was assessed in WT and KO neurons by Sholl analysis, which provides a measure of neuronal arbors’ complexity, and calcium imaging, that analyses the Ca2+ transients in response to glutamatergic stimuli, respectively. Results: Our preliminary results identified a promising compound that rescued autophagy deficits in Mecp2-null neurons and ameliorated morphological and functional alterations. Conclusions: Our results will provide the basis for the treatment of neurological diseases with impaired autophagy function.