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.

脆性 X 智力迟钝蛋白 (FMRP) 的缺失导致脆性 X 综合征 (FXS)，这是最常见的遗传性智力障碍。FMRP 的缺失如何改变蛋白质表达和星形胶质细胞功能仍然基本上未知。在这里，我们发现星形胶质细胞 FMRP 在体内的选择性缺失上调了小鼠和人类 FMRP 缺陷型星形胶质细胞中富含大脑的 miRNA，miR-128-3p，从而抑制了星形胶质细胞代谢型谷氨酸受体 5 (mGluR5) 的发育表达。介导发育星形胶质细胞与神经元通讯的主要受体。在 FMRP 缺陷型星形胶质细胞中选择性体内抑制 miR-128-3p 足以挽救 mGluR5 功能下降，而 miR-128-3p 的星形胶质细胞过表达强烈且选择性地减少发育中的星形胶质细胞 mGluR5 信号传导。随后的转录组和蛋白质组分析进一步表明，FMRP 通常并优先通过转录后而非转录机制在星形胶质细胞中调节蛋白质表达。总体而言，我们的研究定义了一种依赖 FMRP 的细胞自主 miR 通路，该通路选择性地改变发育星形胶质细胞 mGluR5 信号传导，揭示了 FXS 发病机制中涉及的星形胶质细胞分子机制。