Microglial GPR56 is the molecular target of maternal immune activation-induced parvalbumin-positive interneuron deficits
Diankun Yu, Tao Li, Jean-Christophe Delpech, Beika Zhu, Priya Kishore, Tatsuhiro Koshi, Rong Luo, Karishma Pratt, Galina Popova, Tomasz J. Nowakowski, Saul Villeda, Xianhua Piao
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 Gpr56 expression in fetal brains in an interleukin-17a–dependent manner and that conditional deletion of microglial Gpr56 [ Gpr56 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 Gpr56 cKO impair interneuron generation. Genetically restoring Gpr56 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.