Summary/Abstract
Down Syndrome (DS) affects over 200,000 individuals in the United States and is the most common genetic
cause of intellectual and developmental disabilities in children and young adults. Down Syndrome arises from
an extra third copy of chromosome 21, encompassing over 200 genes, which leads to genome wide
transcriptional disruption. The brain cell-type specific contribution to DS neurodevelopmental deficits and the
interaction between cognitive and immune dysfunction in DS are poorly understood. DS has been difficult to
model due to limitations in murine orthologs and inadequacies of in vitro systems in modeling complex cellular
interactions. Microglial pathology has been identified in individuals with DS, but the extent to which microglial
dystrophy contributes to neurodevelopmental deficits is unknown. There is increasing evidence for the impact of
microglia on brain development and microglia have been suggested as a novel therapeutic target in DS. This
proposal is built around the central hypothesis that trisomy 21 causes microglial dysfunction and thereby
contributes to the pathogenesis of intellectual and developmental disability in DS. Motivated by our strong
preliminary data that in vitro microglia exhibit altered gene expression and functional phenotypes in
neurodegenerative diseases and psychiatric disorders, we developed novel organoid microglia cocultures and
a chimeric human microglia mouse model, whereby 80% of microglia are human in origin. Here we apply
innovative in vitro and in vivo methods to ascertain the contribution of human DS microglia in neurodevelopment,
neuronal function, and cognition. The project goal is to test the hypothesis that isolated trisomy 21 in human
microglia and microglia-cerebral organoid cocultures in vitro (Aim 1) and in a xenotransplantation model of
human microglia in vivo (Aim 2) results in microglial pathology, neuropathological defects, and behavioral
deficits. Delineating genome wide transcriptional disruption and genome wide reorganization will uncover DS
associated transcriptional dysregulation and expand our knowledge of DS associated genes. The long-term
goal is to generate and validate in vitro and in vivo DS microglial models that can be employed for drug screening
and to generate preclinical data. A deeper understanding of the contribution and molecular regulation of microglia
in DS will lay the groundwork to ultimately identify novel potential therapeutic targets to improve the outcomes
for individuals with DS.