LAUSR

Inactivation of the Fmr1 gene that is mutated in fragile X syndrome leads to loss of retinoic acid–mediated homeostatic plasticity in human neurons. A fragile neuronal network Inactivation of the fragile X mental retardation 1 (FMR1) gene leads to fragile X syndrome, the most common genetic neurodevelopmental disorder involving severe intellectual disabilities. However, the effects of FMR1 inactivation on neuronal functions are not well understood. Zhang et al. show that homeostatic synaptic plasticity, the mechanism responsible for optimization of neuronal network activity, was abolished in human neurons generated from fragile X patient-derived induced pluripotent stem cells. The inhibition of homeostatic synaptic plasticity was mediated by inhibition of retinoic acid signaling. The results underscore the relevance of neurons derived from patient-derived induced pluripotent stem cells for understanding disease pathogenesis and suggest that reactivation of retinoic acid signaling might be a beneficial therapeutic strategy for fragile X syndrome. Fragile X syndrome (FXS) is an X chromosome–linked disease leading to severe intellectual disabilities. FXS is caused by inactivation of the fragile X mental retardation 1 (FMR1) gene, but how FMR1 inactivation induces FXS remains unclear. Using human neurons generated from control and FXS patient-derived induced pluripotent stem (iPS) cells or from embryonic stem cells carrying conditional FMR1 mutations, we show here that loss of FMR1 function specifically abolished homeostatic synaptic plasticity without affecting basal synaptic transmission. We demonstrated that, in human neurons, homeostatic plasticity induced by synaptic silencing was mediated by retinoic acid, which regulated both excitatory and inhibitory synaptic strength. FMR1 inactivation impaired homeostatic plasticity by blocking retinoic acid–mediated regulation of synaptic strength. Repairing the genetic mutation in the FMR1 gene in an FXS patient cell line restored fragile X mental retardation protein (FMRP) expression and fully rescued synaptic retinoic acid signaling. Thus, our study reveals a robust functional impairment caused by FMR1 mutations that might contribute to neuronal dysfunction in FXS. In addition, our results suggest that FXS patient iPS cell–derived neurons might be useful for studying the mechanisms mediating functional abnormalities in FXS.