The sheep as a translational model for neurodevelopmental disorders induced by prenatal maternal immune activation

Neurodevelopmental disorders (ND) arise from a complex interaction between genetic and maternal environmental factors occurring during pregnancy and involving the immune system. Rodent models, particularly genetic and immune-based approaches, have significantly advanced our understanding of ND etiology and pathogenesis. However, translationally relevant large animal model of maternal immune activation, capable of recapitulating behavioral phenotypes and biomarker associations consistent with ND are missing. In this study, we aimed to model ND in sheep by inducing Maternal Immune Activation (MIA) in pregnant ewes, as prenatal infections are well-replicated environmental factors associated with an increased risk of ND in humans. Pregnant ewes were challenged with bacterial lipopolysaccharide (LPS) to induce MIA at either mid- or late pregnancy, and the lambs' behaviors were monitored after birth. Moreover, we developed and validated a battery of behavioral assays (e.g., Isolation Test, V-Detour Test, and T-Maze) to assess ND-related behavioral domains in lambs, such as social attachment, spatial learning, inhibitory control, and cognitive flexibility. Lambs prenatally exposed to MIA exhibited selective impairments in cognitive domains, including learning, memory consolidation, and cognitive flexibility, while developmental milestones and core social behaviors, such as maternal bonding, remained unchanged. Importantly, individual differences in maternal inflammatory responses, particularly IL-6 levels, correlated with the severity of behavioral alterations in the offspring. The observed behavioral phenotypes and immunological correlations support the validity of the ovine model for studying ND and related behavioral disorders. Our findings lay the groundwork for using sheep in future mechanistic and preclinical research on neurodevelopmental disorders.