Neuroimmune and behavioral changes elicited by maternal immune activation in mice are ameliorated by early postnatal immune stimulation

Abstract

Though the etiology of autism spectrum disorder (ASD) is complex and not fully understood, it is believed that genetic risk factors, coupled with early life inflammation may predispose individuals to develop ASD. Maternal immune activation (MIA) is associated with increased incidence of ASD in offspring; however, not all mothers who experience inflammation during pregnancy have children with autism, suggesting that MIA may act as a disease primer that results in ASD pathology when paired with additional inflammatory insults. Here, we tested the hypothesis that MIA is a disease primer by using a two-hit model that combined MIA with a secondary immune stimulation in early life. C57BL/6J mouse dams were treated with polyinosinic-polycytidylic acid (Poly(I:C)) at embyronic day 12.5, and a subset of litters were then treated with the endotoxin lipopolysaccharide (LPS) four days after birth. Offspring were assessed in young adulthood for changes in behavior including sociability, repetitive-like behaviors, and anxiety-like behaviors. Flow cytometry was performed in adulthood to assess changes in immune cell populations in the periphery and in the brain. MIA increased repetitive-like behaviors in male mice and decreased sociability in both sexes. Unexpectedly, the secondary immune stimulation with LPS did not exacerbate changes in social and repetitive-like behaviors in either sex. MIA also altered distribution of cytotoxic CD8 + T cell populations in the periphery and brain of both sexes: CD8 + T cells were elevated in thymus but reduced in spleen, lymph, and brain. Additionally, MIA altered microglia activity in a region-specific manner in male mice, which was also not exacerbated but rather ameliorated when combined with LPS. Our results demonstrate that changes in repetitive-like and social behaviors that are induced by MIA in male mice are not exacerbated by subsequent inflammatory challenge and highlights the importance of considering the timing of stressors in the appearance of developmental pathology.

Keywords: Autism; Maternal immune activation; Microglia; T cell; Two-hit.