A two-hit model of autism in female mice: effects on behavior and neuroinflammation

SEIFFE, ARACELI; DEPINO, AMAICHA M.

Davis

Simposio; Symposium on Neuro-Immune Interactions; 2021

Autism spectrum disorders (ASD) are characterized by reduced sociability, diminished communicative skills and repetitive behaviors. Notably, the proportion between boys and girls diagnosed with ASD is 4:1 approximately. This suggests a higher susceptibility in boys to develop this disorder, or a resilience in girls. To identify the biological mechanisms acting in female animals that could underlie this bias, we used a mouse model of ASD: the prenatal exposure to valproic acid (VPA). Recently, we observed that this model presents a different phenotype in males and females, as females do not show the reduction in sociability observed in adult males. While the etiology of ASD remains heterogeneous, one important risk factor is immune system dysregulation. In fact, in the VPA model we found immunological alterations in VPA female mice: an increase in astrocyte and microglia density in the hippocampus and a decrease in the cerebellum between postnatal days (PD) 21 and 35. Using a two-hit model, that consists in prenatal VPA exposure and a chronic treatment with peripheral LPS between PD 21 and 35, we found that female mice show a reduction in sociability. This evidence suggests that sex differences observed in the immune cell density during the juvenile period could underlie the resilience observed in VPA females. Moreover, we show that a second stimulus (LPS) is sufficient to elicit social alterations and other characteristics related to ASD, overcoming the sex-dependent resilience. Finally, we analyzed immune cell density in the hippocampus and cerebellum in our two-hit model.We hope that this study will help us identify a possible biological mechanism underlying the effects of prenatal VPA exposure on glial cell density, peripheral inflammatory response and/or behavior.