Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation

Abstract

Infectious or noninfectious maternal immune activation (MIA) is an environmental risk factor for psychiatric and neurological disorders with neurodevelopmental etiologies. Whilst there is increasing evidence for significant health consequences, the effects of MIA on the offspring appear to be variable. Here, we aimed to identify and characterize subgroups of isogenic mouse offspring exposed to identical MIA, which was induced in C57BL6/N mice by administration of the viral mimetic, poly(I:C), on gestation day 12. Cluster analysis of behavioral data obtained from a first cohort containing >150 MIA and control offspring revealed that MIA offspring could be stratified into distinct subgroups that were characterized by the presence or absence of multiple behavioral dysfunctions. The two subgroups also differed in terms of their transcriptional profiles in cortical and subcortical brain regions and brain networks of structural covariance, as measured by ex vivo structural magnetic resonance imaging (MRI). In a second, independent cohort containing 50 MIA and control offspring, we identified a subgroup of MIA offspring that displayed elevated peripheral production of innate inflammatory cytokines, including IL-1β, IL-6, and TNF-α, in adulthood. This subgroup also showed significant impairments in social approach behavior and sensorimotor gating, whereas MIA offspring with a low inflammatory cytokine status did not. Taken together, our results highlight the existence of subgroups of MIA-exposed offspring that show dissociable behavioral, transcriptional, brain network, and immunological profiles even under conditions of genetic homogeneity. These data have relevance for advancing our understanding of the variable neurodevelopmental effects induced by MIA and for biomarker-guided approaches in preclinical psychiatric research.

Symptomatic and preventive effects of the novel phosphodiesterase-9 inhibitor BI 409306 in an immune-mediated model of neurodevelopmental disorders

“…Our study did not provide any evidence for sex-dependent effects of MIA and/or BI 409306 treatment. In keeping with the fact that maternal poly(I:C) administration was conducted on GD 12, the lack of sex-dependent MIA effects is consistent with our previous findings, showing that poly(I:C)-induced MIA in early or middle gestation (GD 9 or 12) mostly failed to induce robust sexspecific effects on behavior [24,26,30], whereas identical MIA at a later gestational time period (e.g., GD 17) is associated with remarkable sex-specific effects [31]. Hence, the precise prenatal timing appears to be one of the factors determining the extent to which poly(I:C)-induced MIA produces sex-dependent or -independent effects on behavior.…”

“…Social interaction was assessed using the relative time spent exploring an unfamiliar congenic mouse and an inanimate dummy object in a modified Y-maze, as described previously [ 26 , 27 ]. During each trial, the mouse was allowed to explore the maze freely for 5 min.…”

“…Sensorimotor processing was assessed using PPI of the acoustic startle reflex, as described previously [ 26 , 28 ]. Animals were presented with a mixture of prepulse-only trials, pulse-only trials, prepulse–plus–pulse trials, and no stimulus trials.…”

“…The MIA model was implemented as previously reported [23][24][25][26] and full details are provided in Supplementary Table S1. In brief, successful mating was verified by the presence of a vaginal plug (designated as gestational day [GD] 0).…”

“…Pharmacokinetic study Male C57Bl6/N mice (10-12 weeks of age; Charles River Laboratories, Sulzfeld, Germany) were orally administered with BI 409306 0.5 mg/kg via MDA. Blood samples were taken via tail-vein sampling after 0.5, 1, and 2 h in 1.5 mL ethylenediaminetetraacetic acid (EDTA)-containing tubes and centrifuged (10,000 × g) for 10 min at 4°C, as described previously [26]. The resulting plasma was stored at −20°C.…”