Maternal Interleukin-4 and allergic asthma in mouse offspring behavioral deficits

Mount Holyoke College, South Hadley MA

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Abstract

PROJECT SUMMARY/ABSTRACT The state of the mother's immune system during pregnancy plays an important role in fetal development, and disruptions in this immune balance are associated with a range of neuropsychiatric and neurodevelopmental disorders. Epidemiological and clinical studies have revealed associations between neurodevelopmental disorders including Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) and family history of immune system dysfunction, most notably allergies and asthma. Over the past three decades, analogous increases have been reported in both the incidence of ASD, ADHD, and immune-related disorders, particularly immune hypersensitivities that include allergies and asthma. Several case-control reports have noted that mothers with elevated allergic-associated cytokines during pregnancy are at greater risk of having a child who was later diagnosed with ASD or ADHD. These data raise the hypothesis that maternal allergic asthma (MAA) produces neurobehavioral deficits in offspring and highlight a yet undetermined link between the maternal immune system and risk of neurodevelopmental disorders. Using a validated mouse model of allergic asthma, we have demonstrated that offspring of MAA dams exhibit behavioral deficits characterized by decreased social interactions and increased repetitive behaviors. This proposal will extend these findings by exploring the mechanistic contribution of the allergic asthma-associated cytokine interleukin-4 (IL-4) in driving the link between MAA on offspring brain and behavior development. Specifically we will [1] determine the contribution of maternal IL-4 signaling in precipitating neurodevelomental deficits, [2] characterize the safety and efficacy of the allergic asthma medication dupilumab, an IL-4 receptor antagonist, in preventing the effects of MAA on offspring behavior, [3] examine the neuroimmunological consequences of MAA on offspring brain development, and [4] associate changes in neuroimmune signaling with behavioral outcomes. The results of these experiments will determine the extent to which maternal IL-4 signaling in allergic asthma contributes to offspring neurodevelopmental deficits and inform future therapeutic interventions for mitigating the effects of maternal asthma in at-risk populations.