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

Proc Natl Acad Sci U S A. 2020 Oct 6;117(40):25092-25103. doi: 10.1073/pnas.2014080117. Epub 2020 Sep 21.


The loss of fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS), the most common inherited intellectual disability. How the loss of FMRP alters protein expression and astroglial functions remains essentially unknown. Here we showed that selective loss of astroglial FMRP in vivo up-regulates a brain-enriched miRNA, miR-128-3p, in mouse and human FMRP-deficient astroglia, which suppresses developmental expression of astroglial metabotropic glutamate receptor 5 (mGluR5), a major receptor in mediating developmental astroglia to neuron communication. Selective in vivo inhibition of miR-128-3p in FMRP-deficient astroglia sufficiently rescues decreased mGluR5 function, while astroglial overexpression of miR-128-3p strongly and selectively diminishes developmental astroglial mGluR5 signaling. Subsequent transcriptome and proteome profiling further suggests that FMRP commonly and preferentially regulates protein expression through posttranscriptional, but not transcriptional, mechanisms in astroglia. Overall, our study defines an FMRP-dependent cell-autonomous miR pathway that selectively alters developmental astroglial mGluR5 signaling, unveiling astroglial molecular mechanisms involved in FXS pathogenesis.

Keywords: FMRP; astroglia; fragile X syndrome; mGluR5; miR-128.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Syndrome / genetics*
  • Fragile X Syndrome / pathology
  • Humans
  • Mice
  • MicroRNAs / genetics*
  • Neurons / metabolism
  • Receptor, Metabotropic Glutamate 5 / genetics*
  • Signal Transduction / genetics
  • Transcriptional Activation / genetics


  • FMR1 protein, human
  • Grm5 protein, mouse
  • MIRN128 microRNA, human
  • MicroRNAs
  • Receptor, Metabotropic Glutamate 5
  • Fragile X Mental Retardation Protein