Selective Timing of Maternal Immune Activation Alters Developmental Milestones, Behavior, and Blood-Brain Barrier Integrity

Abstract

Background and Hypothesis: Maternal immune activation (MIA) has been associated with increased risk for neuropsychiatric disease. Fetal exposure to maternal infection activates different toll-like receptors (TLRs) to initiate innate inflammatory responses in mother and fetus. The goal of the current study is to determine sex-dependent aspects of MIA during mid-gestation on neurodevelopment. Methods: Timed-pregnant female mice were administered RQ (TLR7 agonist) or vehicle saline on embryonic day (E) 12.5. Maternal and fetal cytokines were measured to ensure infection of pregnant dam (E15). Offspring were assessed postnatally for developmental milestones and behavior. Adult offspring were perfused with fluorescein isothiocyanate (FITC; 100mg/mL) to visualize blood vessel integrity (FITC leakage; Frahm & Tobet, 2015). To determine neural molecular mechanisms for behavioral changes, sections through the paraventricular nucleus of the hypothalamus (PVN) of offspring were immunolabeled for Glial Fibrillary Acidic Protein (GFAP; astrocytic end feet), Desmin (pericytes) and IBA-1 (microglia). Results: Maternal cytokines IL-6 (p<0.05) and IL-10 (p<0.01) were higher while TNFα (p<0.01) and IL-17 were lower 3 days after RQ-exposure. In fetuses (E15), IL-6 (p<0.05) and IL-17 (p<0.0001) were greater, while IL-10 was higher only in males (p<0.001) exposed to maternal infection. RQ-exposed males also had reduced TNFα (p<0.05). Additionally, RQ-exposed offspring had lower body weights at birth and delayed eye openings. Females exposed to maternal RQ exhibited slower onset of puberty with delayed vaginal openings. On the behavioral side, juvenile and adult offspring of RQ injected moms exhibited less social-like behavior (p<0.001 for all groups) with lower hedonic-like behavior selectively in females (p<0.001). RQ-offspring further showed greater leakage in the PVN indicated by more FITC in the extravascular space (males p<0.001, females p<0.01). GFAP + (astrocytic end feet) coverage of FITC-labeled vessels was higher in the PVN selectively in RQ males (p<0.001). Desmin+ (pericyte) coverage was greater in the PVN of RQ males (p<0.01) and females (p<0.001). Finally, there was greater number of IBA-1+ cells in the adult offspring PVN of both sexes (p<0.01) after maternal injection of RQ. Conclusions: This study provides support for sex-dependent influences of fetal antecedents for altered brain development and behavioral outputs that could be indicative of increased susceptibility for adult disorders through immune mechanisms. Future studies will examine how timing of infection during gestation (mid vs. late) changes neurodevelopmental outputs in offspring. Supported by ORWH-NIMH U54 SCORE-MH118919. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.