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

Researchers studied mouse offspring from mothers who had immune system activation during pregnancy (a model for autism risk). These offspring showed social difficulties and memory problems at 3 months old. A treatment that renewed brain immune cells helped differently in males versus females - improving social behavior only in males and spatial memory only in females. This suggests autism treatments may need to be tailored differently for boys and girls.

This preclinical study investigated sex-specific behavioral abnormalities in offspring from maternal immune activation (MIA) mouse models and potential therapeutic interventions. MIA was induced during pregnancy using Poly(I:C) injection, resulting in autism-like behaviors in 3-month-old offspring. Both male and female offspring showed impaired sociability and associative memory, while spatial working memory deficits were female-specific. Treatment with CSF1R inhibitor, which renews brain microglia, showed sex-specific therapeutic effects: improving sociability only in males and spatial working memory only in females.

Transcriptomic analysis revealed distinct molecular pathways affected by MIA in each sex, with synaptogenesis pathways in males and cholesterol biosynthesis in females.

This preclinical research suggests future autism interventions targeting microglial function may need sex-specific approaches. However, translation from mouse models to clinical applications requires extensive further research including safety studies and human trials before any therapeutic applications.

Animal model findings may not directly translate to humans. Sample size not reported. Single-dose intervention protocol. Long-term effects of CSF1R inhibition unknown. Limited to specific age timepoint (3 months). Behavioral assessments limited to selected domains.

We 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.