Research ArticleFRAGILE X SYNDROME

Functional changes of AMPA responses in human induced pluripotent stem cell–derived neural progenitors in fragile X syndrome

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Sci. Signal.  16 Jan 2018:
Vol. 11, Issue 513, eaan8784
DOI: 10.1126/scisignal.aan8784

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Calcium-permeable AMPARs in FXS

The intellectual disability disorder FXS (fragile X syndrome) is associated with changes in neuronal function and circuitry in the brain that impair synaptic plasticity, which is critical to learning. Among these changes are increased excitability, impaired maturation of neural structures, and altered differentiation of neural stem cells. To explore these phenotypes in human neurons, Achuta et al. engineered neuronal progenitors from human primary fibroblasts. In those derived from boys with FXS, the expression of the AMPA receptor subunit GluA2 was decreased, which resulted in a greater number of AMPA receptors that lacked GluA2 and thus facilitated increased calcium influx into the cells. Pharmacologically blocking GluA2-lacking AMPA receptors in FXS-derived cultures and in FXS mouse models restored normal neuronal function and phenotypes. The decrease in GluA2 may be mediated by the abnormal abundance or mislocalization of a repressive microRNA due to loss of the RNA binding protein FMRP, which causes FXS.