Loss of FMRP in microglia promotes degeneration of parvalbumin neurons and audiogenic seizures via progranulin insufficiency.

Fragile X syndrome (FXS) results from loss of FMR1-encoded FMRP and is associated with reduced density of parvalbumin (PV) neurons; however, the mechanism underlying this abnormality remains unknown. Here we report that microglial FMRP regulates PV neuron density through lysosomal function. Mice with Fmr1 deletion in microglia exhibited audiogenic seizures (AGS) and decreased PV neuron density in the cortex and AGS-associated inferior colliculus (IC). FMRP increased the expression of lysosomal genes in microglia, including the progranulin-encoding Grn gene. Its loss in microglia led to impaired lysosomal function and increased apoptosis in microglia and PV neurons. Furthermore, PV neuron density in the IC was reduced similarly in male Grn (+/-), Fmr1 (-/y), and Grn (+/-);Fmr1 (-/y) mice, and AAV8-mediated overexpression of progranulin rescued AGS and PV neuron loss in Fmr1 (-/y) mice. This indicates that progranulin insufficiency is a determinant for PV neuron loss in FXS and elevating progranulin is a therapeutic strategy for FXS.