A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem Cells

SummaryAutism spectrum disorders (ASD) are complex neurodevelopmental diseases in which different combinations of genetic mutations may contribute to the phenotype. Using Rett syndrome (RTT) as an ASD genetic model, we developed a culture system using induced pluripotent stem cells (iPSCs) from RTT patients' fibroblasts. RTT patients' iPSCs are able to undergo X-inactivation and generate functional neurons. Neurons derived from RTT-iPSCs had fewer synapses, reduced spine density, smaller soma size, altered calcium signaling and electrophysiological defects when compared to controls. Our data uncovered early alterations in developing human RTT neurons. Finally, we used RTT neurons to test the effects of drugs in rescuing synaptic defects. Our data provide evidence of an unexplored developmental window, before disease onset, in RTT syndrome where potential therapies could be successfully employed. Our model recapitulates early stages of a human neurodevelopmental disease and represents a promising cellular tool for drug screening, diagnosis and personalized treatment.PaperFlick To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon belowHelp with MOV filesOptionsDownload video (23110 K)

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► Rett syndrome and control fibroblasts were reprogrammed to a pluripotent stage (iPSC)
► Rett neurons had fewer synapses, reduced spine density, and smaller soma size
► Rett networks had reduced calcium signaling and spontaneous postsynaptic currents
► Rett neurons can be rescued by expression of MeCP2, addition of IGF1, and gentamicin