Department of Cell and Developmental Biology, Sackler Medical...

Fragile X syndrome FXS the most common form of inherited mental retardation is a neurodevelopmental disorder caused by silencing of the FMR1 gene which in FXS becomes inactivated during human embryonic development We have shown recently that this process is recapitulated by in vitro neural differentiation of FX human embryonic stem cells FX-hESCs derived from FXS blastocysts In the present study we analyzed morphological and functional properties of neurons generated from FX-hESCs Human FX neurons can fire single action potentials APs to depolarizing current commands but are unable to discharge trains of APs Their APs are of a reduced amplitudes and longer durations than controls These are reflected in reduced inward Na and outward K currents In addition human FX neurons contain fewer synaptic vesicles and lack spontaneous synaptic activity Notably synaptic activity in these neurons can be restored by coculturing them with normal rat hippocampal neurons demonstrating a critical role for synaptic mechanisms in FXS pathology This is the first extensive functional analysis of human FX neurons derived in vitro from hESCs that provides a convenient tool for studying molecular mechanisms underlying the impaired neuronal functions in FXS SIGNIFICANCE STATEMENT Fragile X syndrome FXS the most common form of inherited mental retardation is caused by silencing of the FMR1 gene In this study we describe for the first time the properties of neurons developed from human embryonic stem cells hESCs that carry the FMR1 mutation and are grown in culture for extended periods These neurons are retarded compared with controls in several morphological and functional properties In vitro neural differentiation of FX hESCs can thus serve as a most relevant system for the analysis of molecular mechanisms underlying the impaired neuronal functions in FXS

Department of Cell and Developmental Biology, Sackler Medical School, Tel-Aviv University, Tel-Aviv 69978, Israel

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Functional Deficiencies in Fragile X Neurons Derived from Human Embryonic Stem Cells