IL-17A blockade following maternal immune activation prevents autism-like brain and behavioural abnormalities in mice

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental condition characterized by impairments in social communication and interaction, accompanied by restricted, repetitive behaviors or interests. Increasing evidence implicates immune dysregulation in the pathogenesis of ASD. Notably, preclinical studies indicate that maternal infection, especially early in pregnancy, and the consequent maternal immune activation (MIA), induce ASD-like neurobehavioral abnormalities in offspring, driven by interleukin-17A (IL-17A) released by T helper 17 cells. We assessed the therapeutic potential of IL-17A antibody administration shortly after MIA induction to mitigate ASD-like phenotypes in both male and female mouse offspring. MIA was induced by administering polyinosinic:polycytidylic acid [Poly(I:C)], a double-stranded RNA analog, to pregnant mice on gestational day 12.5, followed twenty-four hours later by treatment with an IL-17A antibody. Offspring of both sexes underwent behavioral testing across three developmental cohorts, from early neonatal stages to late adolescence, using batteries targeting ASD core symptoms and comorbidities. Furthermore, to gain insight into early MIA-induced molecular changes and the potential efficacy of IL-17A antibody treatment in preventing these effects, hippocampal synaptic and neuroinflammatory markers were analyzed. Prenatal administration of IL-17A antibody significantly attenuated early motor abnormalities and reduced repetitive behaviors selectively observed in MIA male offspring, while mitigating social deficits emerging in late adolescence in both sexes. Importantly, IL-17A antibody administration prevented early MIA-induced alterations in key players of synaptic plasticity and neuroinflammation in both sexes. These findings indicate that early and precisely timed IL-17A blockade represents a promising therapeutic strategy to prevent ASD-like brain and behavioral abnormalities associated with MIA.