The Impact of hiPSC-Derived Microglia in Human Brain Development in Health and Disease

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Abstract The main goal of this project is to determine the contribution of human microglia in the establishment of early neural networks during development in healthy and autistic conditions. Although the exact cause of Autism Spectrum Disorders (ASD) remains unclear, epigenetic, genetic and environmental factors are at play. Given that ASD is a complex multifactorial disorder and that epigenetic modifications have been shown to control microglial phenotypes/plasticity, we hypothesized that microglial epigenetic signature might influence neuronal development. Given that microglia originate in the periphery and later invade the brain, they are most likely the first brain cell type to be exposed to an environmental factor or at least be impacted by the environmental factor given their role as gate keepers of the brain. Therefore, a better understanding of the genetic, environmental or a synergistic impact of both, will pave the way to a better understanding of human neurodevelopment and human microglial roles during this process yielding to the discovery of novel therapeutic targets and efficient therapies for a broad range of neurological disorders including ASD. Thus, with this project, we aim to establish whether and how human microglia interfere with neural network establishment and if high-risk ASD epigenetic genes could alter their function and their role during human neurodevelopment. Based on our preliminary data we propose the following specific aims are: Aim 1: Determine the role of healthy human microglia on healthy brain cortical organoids (BCO), Aim 2: Measure the impact of microglia carrying ASD mutations on BCO development and function, and Aim 3: Impact of environmental ASD-risk factors in combination with underlying genetic predisposition: the two-hit hypothesis. Here we will test the isolated and additive effect of ASD-related environmental factors on the function of microglia and its impact on BCO physiology.