Targeting RORgt activity to prevent the development of ASD-related phenotypes
New York University
The exact cause of autism spectrum disorders (ASD) is still unknown, but accumulating evidence from human and mouse model studies suggest that abnormal function of the immune system may play a key role. Enhanced expression of proinflammatory molecules called cytokines, particularly IL-6, is often found in the blood and postmortem brain of ASD patients. Moreover, exposure to maternal infection and the resulting inflammatory response during pregnancy is a leading environmental risk factor for ASD in the offspring. In mouse models of this risk factor, maternal immune activation (MIA) causes long-term behavioral, neurological and immunological abnormalities in the offspring similar to those in human ASD. MIA induces IL-6, which triggers the expression of other cytokines and genes that regulate the immune system. This in turn is thought to adversely affect fetal development and cause ASD-like symptoms in the offspring. A major player in the IL-6 signaling pathway is a transcription factor that regulates gene expression called RORgt. RORgt is critical for activating IL-17-secreting T helper cells (Th17), which have a protective function against infections. However, inappropriate Th17 activation has been linked to several autoimmune and inflammatory disorders, including ASD. This project will examine the role of RORgt in the display of ASD-like symptoms following MIA in mouse models, with the goal of identifying RORgt as a potential therapeutic target to prevent or treat ASD. Preliminary data supports the idea that RORgt promotes the adverse effects of MIA on ASD development. To test this idea further, RORgt signaling will be inhibited by deleting the gene or using a specific drug in a mouse model of MIA. Behavioral assays will be used to determine if inhibiting RORgt prevents the display of ASD-like behaviors in offspring of mice that experience MIA. Additionally, prenatal treatment with an RORgt inhibitor will be examined to determine if it can rescue MIA-mediated behavioral and immune symptoms associated with ASD in the offspring. This work is important because it aims to refine our understanding of the mechanisms that underlie how MIA contributes to ASD. In doing so, it is expected to provide insight into new medicines or diagnostic markers for testing the effectiveness of treatment options. Consequently, this work is relevant to Autism Speaks’ targeted research area to improve quality of life through more effective medicines for ASD patients.