Allergic fetal priming leads to developmental, behavioral and neurobiological changes in mice

Abstract

The state of the mother's immune system during pregnancy has an important role in fetal development and disruptions in the balance of this system are associated with a range of neurologic, neuropsychiatric and neurodevelopmental disorders. Epidemiological and clinical reports reveal various clues that suggest a possible association between developmental neuropsychiatric disorders and family history of immune system dysfunction. Over the past three decades, analogous increases have been reported in both the incidence of neurodevelopmental disorders and immune-related disorders, particularly allergy and asthma, raising the question of whether allergic asthma and characteristics of various neurodevelopmental disorders share common causal links. We used a mouse model of maternal allergic asthma to test this novel hypothesis that early fetal priming with an allergenic exposure during gestation produces behavioral deficits in offspring. Mothers were primed with an exposure to ovalbumin (OVA) before pregnancy, then exposed to either aerosolized OVA or vehicle during gestation. Both male and female mice born to mothers exposed to aerosolized OVA during gestation exhibited altered developmental trajectories in weight and length, decreased sociability and increased marble-burying behavior. Moreover, offspring of OVA-exposed mothers were observed to have increased serotonin transporter protein levels in the cortex. These data demonstrate that behavioral and neurobiological effects can be elicited following early fetal priming with maternal allergic asthma and provide support that maternal allergic asthma may, in some cases, be a contributing factor to neurodevelopmental disorders.

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

“…Conversely, both FVB/Ant and C57 offspring of OVA-dams engaged in significantly less stereotypical grooming behavior compared to control mice of the same strain. These findings are consistent with previous work characterizing the behavioral effects of maternal allergic asthma (Schwartzer et al, 2015). The discrepancies in these repetitive grooming and marble burying tasks have been previously observed (Muehlmann et al, 2012; Sungur et al, 2014) and underscore the differences in neuronal mechanisms that drive these behaviors.…”

“…Behavioral measures from MAA offspring corroborate previous mouse model findings linking maternal allergic asthma to altered patterns of restructured/repetitive behaviors (Schwartzer et al, 2015) and extend this model by identifying altered patterns of social interaction present at a juvenile age. Animal models of autism and other neurodevelopmental disorders, including models of maternal immune activation, have relied on the social approach tasks to identify changes in social behavior deficits (Crawley, 2007; Meyer, 2013).…”

“…Using a recently developed animal model of maternal allergic asthma (Schwartzer et al, 2015), pregnant dams of two immunologically distinct backgrounds (i.e. C57 and FVB) underwent repeated OVA-inductions and their sera analyzed for differences in immunogenic phenotype between the two strains.…”

“…Pregnant mice were exposed to either an aerosolized solution of 1% (wt/vl) OVA in PBS (OVA group) or PBS control for three 45-minute induction sessions throughout gestation. Specifically, these induction sessions occurred at gestational days 9.5, 12.5, and 17.5, to correspond with early, middle, and late gestation as previously described (Schwartzer et al, 2015). Four hours after the final induction, 100µl of blood was drawn and collected from the saphenous vein for cytokine analysis and mice were returned to their home cages, single housed, and left undisturbed until the birth of their litters.…”

“…Though ASD is a strictly human disorder, several indicative behaviors like repetitive stereotypies or social avoidance can be modeled in mice (Silverman et al, 2010). One novel model precipitates ASD-like behavioral deficits in offspring exposed to maternal allergic asthma (MAA) (Schwartzer et al, 2015); this model sensitizes female mice to ovalbumin (OVA) protein followed by induction of airway hypersensitivity through aerosolized OVA exposure at gestational days (G)9.5, 12.5, and 17.5 to mimic early, middle, and late gestation in humans. Importantly, variations in genetic background between mouse strains result in varying severity of immune responses to allergic asthma induction.…”