Maternal immune activation in mice recapitulates features of attention-deficit/hyperactivity disorder (ADHD) in susceptible offspring

Prenatal exposure to infectious or non-infectious maternal immune activation (MIA) represents a transdiagnostic environmental risk factor for psychiatric and neurodevelopmental disorders. Building on previous findings of locomotor hyperactivity in a subset of male MIA offspring, the present study investigated whether viral-like MIA in mice recapitulates features of attention-deficit/hyperactivity disorder (ADHD) in this subgroup. We show that 40-50% of MIA-exposed male offspring develop locomotor hyperactivity in a novel environment, which is most pronounced during early- to mid-adolescence and precedes the emergence of increased impulsive behavior and pre-attentive filtering deficits in early adulthood. We further identified subgroup-specific dopaminergic and noradrenergic alterations in cortical and subcortical brain regions of MIA offspring. These neuronal alterations were age-dependent and correlated with behavioral changes. Moreover, treatment with methylphenidate (MPH), a first-line pharmacological therapy for ADHD, normalized locomotor hyperactivity and restored abnormal mesolimbic and striatal activation patterns in susceptible MIA offspring. Collectively, our findings demonstrate that MIA in mice recapitulates key features of ADHD in a susceptible subset of offspring, supporting the notion that MIA may contribute etiologically to ADHD in some individuals. More broadly, our results suggest that the heterogeneous neurobehavioral outcomes of MIA offspring may result from distinct yet overlapping pathophysiological mechanisms across neurodevelopmental and psychiatric disorders.