Adverse effects of prenatal environmental insults on neurodevelopment: early interventions to reverse neurobehavioral abnormalities in murine models

Central nervous system development is a highly regulated process in which neural plasticity functions as the primary mechanism for adaptation to environmental influences. While elevated neural plasticity is crucial for brain maturation, it also increases fetal susceptibility to adverse stimuli during critical developmental periods. As a result, plasticity not only facilitates adaptation but may also contribute to deviations from typical developmental trajectories following prenatal environmental insults, potentially resulting in neurodevelopmental disorders such as autism spectrum disorder (ASD). Investigating the impact of these insults and identifying critical periods for early intervention remain major challenges in current research. Accordingly, this project evaluated the effectiveness of preventive strategies in two established environmentally induced mouse models of ASD, leveraging the prenatal period as a therapeutic window to restore neurobiological imbalance. The first study investigated the effects of maternal immune activation (MIA) induced by prenatal administration of polyinosinic:polycytidylic acid [Poly(I:C)], characterizing behavioral phenotype throughout development alongside early neuroinflammatory and synaptic plasticity alterations. Given that the proinflammatory cytokine IL17A is a recognized mediator of MIA-induced abnormalities, the study evaluated the therapeutic potential of early administration of IL17A antibody following MIA induction to mitigate ASD-like phenotypes in both male and female offspring. Our findings demonstrated that anti-IL17A treatment significantly prevented MIA-induced deficits in behavior, synaptic plasticity, and neuroinflammation, suggesting that early and targeted blockade of the IL17A pathway may offer a promising approach to counteracting ASD-like alterations associated with MIA. The second study investigated the neurobehavioral effects of prenatal exposure to the antiepileptic drug valproic acid (VPA) in offspring, a validated model of ASD. Among the mechanisms by which administration of VPA in pregnancy may increase the risk of ASD, its histone deacetylase inhibitory action has attracted considerable attention. Notably, recent evidence suggests that S-adenosylmethionine (SAM), a key methyl donor, has the potential to prevent gene expression alterations induced by VPA. This study evaluated whether prenatal administration of SAM could counteract the ASD-like behavioral phenotypes induced by VPA exposure in offspring. Results demonstrated that VPA selectively induced increased repetitive behaviors and executive function deficits in male offspring, phenotypes that were effectively restored by SAM. These findings suggest that early SAM supplementation may attenuate specific behavioral effects of prenatal VPA exposure, highlighting the potential of epigenetically-targeted interventions in mitigating ASD-related phenotypes. In conclusion, understanding the molecular mechanisms underlying atypical neurobehavioral trajectories induced by prenatal insults enables the identification of therapeutic targets and windows of opportunity. Early, targeted modulation of these pathways may transform developmental vulnerability into an opportunity to prevent neurodevelopmental disorders.