Sex specific correction of maternal inflammation-induced behavioral abnormalities by the inhibition of colony-stimulating factor 1 receptor

Abstract

International audienceWe have previously reported the therapeutic effect of depletion and renewal of endogenous microglia on autism spectrum disorder-like behaviors in offspring from the dams under maternal immune activation (MIA) by dampening their neuritogenic activation. Here we show a long-lasting pathological effect by MIA, leading to abnormal behaviors in offspring mice in a sex-specific manner at 3 months of age. MIA are induced by injecting Polyinosinic:polycytidylic acid [Poly(I:C)] at 10 mg/kg at E9.5 with preselected dams based on the immunoreactivity to low-dose Poly(I:C) injection. MIA offspring show impairments in sociability and associative memories in both sexes, whereas spatial working memory deficit was observed only in females. MIA does not affect social novelty, novel object recognition, anxiety-like behavior nor sensori-motor or locomotor activity. Administering colony-stimulating factor receptor (CSF1R) inhibitor in young adult MIA offspring renews microglia and ameliorates sociability deficits only in males, and spatial working memory only in females while associative memory impairments are reversed in males and partially restored in females. Transcriptomic analysis of prefrontal cortex and hippocampal tissues reveals synaptogenesis and cholesterol biosynthesis as male and female specific MIA pathways respectively, underpinning sex-dependent response to CSF1R inhibitor treatment. Our results reveal the sex specific therapeutic applications of CSF1R inhibitor for MIA-related social and cognitive disorders