Astroglial FMRP deficiency cell-autonomously up-regulates miR-128 and disrupts developmental astroglial mGluR5 signaling

Significance How the loss of FMRP affects nonneuronal glial development especially underlying mechanisms remains essentially unexplored. By employing astroglialFmr1 conditional knockout (cKO) mice and human FMRP-deficient astroglia, in the current study, we showed that the loss of astroglial FMRP cell-autonomously up-regulates brain enriched miR-128-3p in mouse and human FMRP-deficient astroglia, which selectively disrupts developmental astroglial (but not neuronal) mGluR5 signaling. Subsequent transcriptome and proteome profiling from in vivo isolated FMRP-deficient astroglia further indicates that FMRP commonly and preferentially regulates protein expression through posttranscriptional (but not transcriptional) mechanisms (such as miR) in astroglia. Overall, our study defines an FMRP-dependent cell-autonomous miR pathway that alters developmental astroglial mGluR5 signaling, which unveils astroglia-specific molecular mechanisms involved in FXS pathogenesis.