Early IL17A blockade following maternal immune activation prevents behavioral abnormalities, hippocampal synaptic changes and neuroinflammation in male and female offspring

Autism Spectrum Disorder (ASD) is marked by impairments in social communication and interaction, alongside repetitive behavior, with increasing evidence implicating immune dysregulation in its pathogenesis. Preclinical studies indicate that infections during pregnancy and resultant maternal immune activation (MIA) induces ASD- like neurobehavioral abnormalities in offspring, involving interleukin-17A (IL17A) released by T helper 17 cells. Here, we evaluated the potential efficacy of early administration of IL17A antibody shortly after MIA induction to mitigate ASD-like phenotypes focusing on both male and female mouse offspring. MIA was induced by administering polyinosinic:polycytidylic acid [Poly(I:C)] to pregnant mice on gestational day 12.5. Twenty-four hours later, mice were injected with IL17A antibody (anti-IL17A). Offspring were divided into three developmental cohorts (neonatal, early adolescence, and late adolescence), each tested with a tailored behavioral battery relevant to ASD. Additionally, to get further insight into MIA-induced molecular changes and the potential efficacy of anti-IL17A treatment in preventing these effects, hippocampal synaptic and neuro- inflammatory markers were analyzed at postnatal day 28. Prenatal administration of anti-IL17A significantly attenuated repetitive behavior selectively observed in MIA male offspring and mitigated social deficits emerging in late adolescence in both sexes. Importantly, anti-IL17A administration prevented in both sexes early MIA-induced alterations in key players of synaptic plasticity (i.e. brain derived neurotrophic factor, synaptic proteins, glutamate receptor NMDA) and neuroinflammation. Early and precisely timed blockade of IL17A (24 h after MIA-induction) represents a promising prophylactic strategy to prevent ASD-like brain and behavioral abnormalities associated with MIA.