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.

Abstract

Altered neuronal network formation and function involving dysregulated excitatory and inhibitory circuits are associated with fragile X syndrome (FXS). We examined functional maturation of the excitatory transmission system in FXS by investigating the response of FXS patient–derived neural progenitor cells to the glutamate analog (AMPA). Neural progenitors derived from induced pluripotent stem cell (iPSC) lines generated from boys with FXS had augmented intracellular Ca2+ responses to AMPA and kainate that were mediated by Ca2+-permeable AMPA receptors (CP-AMPARs) lacking the GluA2 subunit. Together with the enhanced differentiation of glutamate-responsive cells, the proportion of CP-AMPAR and N-methyl-d-aspartate (NMDA) receptor–coexpressing cells was increased in human FXS progenitors. Differentiation of cells lacking GluA2 was also increased and paralleled the increased inward rectification in neural progenitors derived from Fmr1-knockout mice (the FXS mouse model). Human FXS progenitors had increased the expression of the precursor and mature forms of miR-181a, a microRNA that represses translation of the transcript encoding GluA2. Blocking GluA2-lacking, CP-AMPARs reduced the neurite length of human iPSC-derived control progenitors and further reduced the shortened length of neurites in human FXS progenitors, supporting the contribution of CP-AMPARs to the regulation of progenitor differentiation. Furthermore, we observed reduced expression of Gria2 (the GluA2-encoding gene) in the frontal lobe of FXS mice, consistent with functional changes of AMPARs in FXS. Increased Ca2+ influx through CP-AMPARs may increase the vulnerability and affect the differentiation and migration of distinct cell populations, which may interfere with normal circuit formation in FXS.

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