Ontogeny and plasticity of resilience and susceptibility in a mouse model of maternal immune activation

Maternal immune activation (MIA) during pregnancy results in variable neurodevelopmental and behavioral outcomes in both humans and animal models. In a mouse model of MIA using prenatal poly(I:C) administration, we recently identified subgroups of MIA-exposed offspring with distinct behavioral and transcriptional profiles even under genetic homogeneity. Here, we used the same model to explore whether the expression of resilient and susceptible phenotypes after MIA represents stable traits or whether they exhibit plasticity throughout adolescent maturation. Conducting longitudinal testing in a first cohort, we revealed that MIA offspring can be stratified into subgroups with distinct behavioral profiles at juvenile age. This early divergence was sex-dependent and predictive of different behavioral outcomes at adult age. In a second cohort, we examined the effects of repeated social intervention during peri-adolescence on brain and behavioral trajectories. In male MIA offspring displaying juvenile deficits in sociability and hyperactivity, the intervention did not alleviate adult deficits in sociability or temporal order memory but prevented the adult emergence of prepulse inhibition impairments. Conversely, in female MIA offspring with juvenile social deficits, the intervention improved adult deficits in sociability and temporal order memory, but it failed to normalize adult impairments in prepulse inhibition. These sex-specific behavioral outcomes were paralleled by subgroup-specific changes in oxytocinergic and dopaminergic markers in cortical and subcortical brain regions. Together, our findings indicate that MIA-exposed offspring can be stratified into distinct subgroups early in life, with subsequent risk and resilience trajectories varying by sex. Moreover, our data identify a window of plasticity during which targeted interventions can modulate abnormal maturational trajectories, ultimately mitigating the long-term effects of MIA in a sex-dependent manner.