A microglial basis for fragile X syndrome via impairment of FMRP-regulated lysosomal function

Silencing of the FMRP-encoding FMR1 gene results in fragile X syndrome (FXS), the most common inheritable intellectual disability and autism. FMRP regulates various neuronal functions but clinical trials targeting neurons have failed, suggesting unrecognized disease mechanisms. We find that mice with selective Fmr1 deletion in microglia exhibit audiogenic seizures (AGS) and parvalbumin (PV) neuron loss, recapitulating two key phenotypes observed in FXS (Fmr1^-/y) mice. By combining snRNA-Seq and RNA immunoprecipitation, we identify several lysosomal mRNAs as FMRP binding targets. FMRP promotes lysosomal protein expression and its deficiency disrupts lysosomal function in microglia. Notably, FMRP depletion reduces Grn-encoded secretory progranulin and increases PV neuron apoptosis in immature brains. PV neuron density is decreased similarly in Grn^+/-, Fmr1^-/y, and Grn^+/-;Fmr1^-/y mice, and progranulin overexpression rescues AGS and PV neuron loss in Fmr1^-/y mice. Thus, our study identifies microglia and progranulin as critical regulators of FXS pathogenesis and potential targets for FXS therapy.