02127nas a2200241   4500000000100000000000100001008004100002260001500043653002600058653003700084100001800121700001900139700001500158700001800173700001600191700001900207700002200226700001700248245013000265856005500395520142100450022001401871       2026                            d  c2026-04-1410aCellular neuroscience10aStem cells in the nervous system1 aTatsuya Osaki1 aChloe Delepine1 aYuma Osako1 aDevorah Kranz1 aApril Levin1 aCharles Nelson1 aMichela Fagiolini1 aMriganka Sur00aEarly differential impact of MeCP2 mutations on functional networks in Rett syndrome patient-derived human cortical organoids  uhttps://www.nature.com/articles/s41467-026-71458-03 aHuman cerebral organoids derived from induced pluripotent stem cells can recapture early developmental processes and reveal changes involving neurodevelopmental disorders. Mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene are associated with Rett syndrome, and disease severity varies depending on the location and type of mutation. Here, we focused on neuronal activity in Rett syndrome patient-derived organoids, analyzing two types of MECP2 mutations—a missense mutation (R306C) and a truncating mutation (V247X)—using calcium imaging with three-photon microscopy. Compared to isogenic controls, we found abnormal neuronal activity in Rett organoids and altered network function based on graph theoretic analyses, with V247X mutations impacting functional responses and connectivity more severely than R306C mutations. These changes paralleled EEG data obtained from patients with comparable mutations. Labeling >/>DLX promoter-driven inhibitory neurons demonstrated differences in activity and functional connectivity of inhibitory and excitatory neurons in the two types of mutations. Transcriptomic analyses revealed HDAC2-associated impairment in R306C organoids and decreased GABAA receptor expression in excitatory neurons in V247X organoids. These findings demonstrate mutation-specific mechanisms of vulnerability in Rett syndrome and suggest targeted strategies for their treatment.  a2041-1723