Behavioral impact of maternal allergic-asthma in two genetically distinct mouse strains

Abstract

Recent population-based studies of expecting mothers identified a unique profile of immune markers that are associated with an increased risk of having a child diagnosed with autism spectrum disorder (ASD). This immune profile, including increased levels of maternal and placental interleukin (IL)-4 and IL-5, is consistent with an immune response found in an allergic-asthma phenotype. Allergies and asthma reflect an imbalance in immune responses including polarization towards T-helper type 2 (TH2) responses, with both genetic susceptibility and environmental factors affecting this T-cell polarization. Mouse strains provide a known and controlled source of genetic diversity to explore the role of genetic predisposition on environmental factors. In particular, the FVB background exhibits a skew towards TH2-mediated allergic-asthma response in traditional models of asthma whereas the C57 strain exhibits a more blunted TH2 polarized phenotype resulting in an attenuated allergic-asthma response. C57BL/6J (C57) and the sighted FVB.129P2-Pde6b(+) Tyr(c-ch)/Ant (FVB/Ant) lines were selected based on their characteristic high sociability and differing sensitivity to TH2-mediated stimuli. Based on the distinct allergy-sensitive immune responses of these two strains we hypothesized that unique developmental consequences would occur in offspring following maternal allergy-asthma exposure. Female C57 and FVB/Ant dams were primed/sensitized with an exposure to ovalbumin (OVA) before pregnancy, then exposed to either aerosolized OVA or PBS-vehicle throughout gestation. Sera from pregnant dams were analyzed for changes in cytokine profiles using multiplex-arrays and offspring were assessed for changes in autism-like behavioral responses. Analysis of maternal sera revealed elevated IL-4 and IL-5 in OVA-treated dams of both strains but only C57 mice expressed increased levels of IL-1β, IL-6, TNFα, and IL-17. Behavioral assessments revealed strain-dependent changes in juvenile reciprocal social interaction in offspring of maternal allergic asthma dams. Moreover, mice of both strains showed decreased repetitive grooming and increased marble burying behavior when born to OVA-exposed dams. Together, these findings support the important role genetic predisposition plays in the effects of maternal immune activation and underscore differences in ASD-like behavioral outcomes across mouse strains.

Microglia from offspring of dams with allergic asthma exhibit epigenomic alterations in genes dysregulated in autism

“…While ASD has a pronounced sex-bias for males, both male and female MAA offspring show similar behavioral phenotypes deficits in social interactions, increased marble burying, and decreased grooming (Schwartzer et al, 2015, 2017). In rodents, adolescent females show increased microglial reactivity compared to males (Schwarz et al, 2012).…”

“…For all experiments female offspring were chosen for analysis due to previously identified increased microglial reactivity at P30 in females compared to males (Schwarz et al, 2012). Female MAA offspring also show a similar behavioral phenotype to male MAA offspring with deficits in social interactions, increased marble burying and decreased grooming (Schwartzer et al, 2015, 2017). …”

“…The MAA paradigm was conducted as previously described (Schwartzer et al, 2015(Schwartzer et al, , 2017. Briefly, on postnatal day (P) 42 and 49 sexually naive female C57Bl/6J mice were sensitized with a single intraperitoneal injection of 10 lg ovalbumin (OVA, Sigma, St. Louis, MO) in 1 mg (Al)OH 3 (InvivoGen, San Diego, CA) dissolved in 200 lL phosphate buffered saline (PBS).…”

“…MAA produced a phenotype in the offspring of impaired social approach and increased repetitive behaviors at both juvenile and adult ages (Schwartzer et al, 2015(Schwartzer et al, , 2017 that resemble behavioral features of ASD (Thomas et al, 2009). MAA challenge in gestation also resulted in altered brain neurochemistry in offspring similar to those observed in ASD (Schwartzer et al, 2015).…”

“…We recently developed the first preclinical model of maternal allergic asthma (MAA) that produces the hallmark immunological responses in the MAA treated dams analogous to those observed in humans, including allergic airway inflammation and elevated levels of IL-4 and IL-5 (Schwartzer et al, 2015). MAA produced a phenotype in the offspring of impaired social approach and increased repetitive behaviors at both juvenile and adult ages (Schwartzer et al, 2015, 2017) that resemble behavioral features of ASD (Thomas et al, 2009). MAA challenge in gestation also resulted in altered brain neurochemistry in offspring similar to those observed in ASD (Schwartzer et al, 2015).…”