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 PV⁺ interneurons in the somatosensory cortex and autism-like behaviors. However, the underlying molecular mechanisms remain largely unknown. Here, we show that MIA down-regulates microglial <i>Gpr56</i> expression in fetal brains in an interleukin-17a-dependent manner and that conditional deletion of microglial <i>Gpr56</i> [<i>Gpr56</i> conditional knockout (cKO)] mimics MIA-induced PV⁺ interneuron 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 and <i>Gpr56</i> cKO impair interneuron generation. Genetically restoring <i>Gpr56</i> expression in microglia ameliorates PV⁺ interneuron deficits and autism-like behaviors in MIA offspring. Together, our study demonstrates that microglial GPR56 plays an important role in PV⁺ interneuron development and serves as a salient target of MIA-induced neurodevelopmental disorders.