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Characterization of Microglial Wnt Signaling in Maternal Immune Activation-Related Autism

There is a pressing need to develop novel therapies for autism spectrum disorders (ASD). Innate immune signaling is emerging as a key novel target, corroborated by mounting evidence implicating its involvement in ASD etiology. Maternal infection during pregnancy and subsequent innate immunity response may play a critical role in the development of ASD. Significantly elevated microglial activation has been shown in the cortical, subcortical and cerebellum regions in postmortem ASD brains, and by live PET imaging of young adult subjects with ASD. However, it remains unknown whether activated microglia are directly involved in neurodevelopmental abnormalities or clinical symptoms of ASD. Dr. Ikezu and colleagues have characterized the molecular interactome of microglia and neural stem cells, and found that Wingless-related MMTV integration site 5a (Wnt5a) is induced by microglial activation and critically induces dendrite arborization. Moreover, silencing of Wnt5a in microglia significantly diminished their effect on neural maturation.

Dr. Ikezu’s central hypothesis is that maternal immune activation (MIA) induces prenatal or perinatal microglial activation and excessive microglial production of neurotrophic factors including Wnt5a in offspring, leading to aberrant local synaptogenesis and axonal guidance during early brain development. His hypothesis has been formulated by exciting preliminary data that Wnt5a gene expression is significantly increased in microglia acutely isolated from MIA-treated embryos or neonates. Dr. Ikezu and colleagues will delineate whether microglia are responsible for particular synaptic abnormalities by assessing the effect of depleting microglia or microgliaspecific molecules in the MIA model of ASD. The results of this research will lead to an entirely novel paradigm for the role of microglia underlying pathobiology of MIA-induced ASD phenotype, and potentially other genetic models of ASD.