Microglial GPR56 is the molecular target of maternal immune activation-induced parvalbumin-positive interneuron deficits.

Abstract

Parvalbumin-positive (PV) interneurons play a critical role in maintaining circuit rhythm in the brain, and their reduction is implicated in autism spectrum disorders. Animal studies demonstrate that maternal immune activation (MIA) leads to reduced PVinterneurons in the somatosensory cortex and autism-like behaviors. However, the underlying molecular mechanisms remain largely unknown. Here, we show that MIA down-regulates microglialexpression in fetal brains in an interleukin-17a-dependent manner and that conditional deletion of microglial[conditional knockout (cKO)] mimics MIA-induced PVinterneuron defects and autism-like behaviors in offspring. We further demonstrate that elevated microglial tumor necrosis factor-α expression is the underlying mechanism by which MIA andcKO impair interneuron generation. Genetically restoringexpression in microglia ameliorates PVinterneuron deficits and autism-like behaviors in MIA offspring. Together, our study demonstrates that microglial GPR56 plays an important role in PVinterneuron development and serves as a salient target of MIA-induced neurodevelopmental disorders.