Autism spectrum disorder (ASD) appears to be caused by both genetic mutations and environmental exposures during early development. Recent work points to a central role for immune-related genes and immune responses to environmental stimuli in ASD. In particular, maternal infection during early gestation is a demonstrated risk factor for ASD. The development of a mouse model of maternal infection has strengthened the link between maternal immune activation (MIA) and ASD. Offspring from pregnant mice that had their immune systems activated during early gestation exhibit the three core behavioral symptoms of autism. Results from this MIA mouse model and recent human studies have converged on the hypothesis that maternal infection changes immune responses in the offspring in ways that alter brain development and behavior, thereby contributing to ASD. Consistent with this idea, we recently discovered that immune proteins are chronically altered in the brains of MIA offspring where they prevent connections from brain cells in newborn offspring from forming correctly. In addition, recent reports have revealed genetic associations between ASD and genes encoding immune molecules and ASD-like behaviors in mice with altered microglial function. Despite these reports, it is not known if these different kinds of immune molecules converge on a common molecular pathway to alter brain connections during postnatal development to cause ASD. In this proposal, we will test the hypothesis that MIA and dysfunctional microglial signaling cause ASD-related behaviors in offspring by altering neural connections via a shared immune signaling pathway in the brain. Information from this project is essential for understanding how the risk factor of MIA leads to ASD-like behaviors in mice and may provide insight into the molecular mechanisms underlying changes in the brains of individuals with neural-immune forms of ASD.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
