The list of developmental events that may lead to intellectual disability in Down syndrome (DS) ranges from the over expression of single genes to altered synaptic and firing properties of neurons throughout the nervous system. Recently, our laboratory has discovered intrinsic defects in oligodendrocyte precursor cell (OPC) maturation that lead to changes in myelination and white matter tract formation in a mouse model of DS. This dysmyelination, confirmed using human brain gene expression profiling and myelin imaging, has been shown to lengthen the time it takes for action potentials to reach their postsynaptic targets. Since this novel cellular defect presumably underlies at least part of the intellectual disability in DS, a straightforward therapeutic approach would be to treat with compounds that promote OPC maturation. Initial results in mouse models look promising, but whether OPCs from humans with DS exhibit the same defects found in mouse model cells is critical for this effort. In this project, we will take advantage of pre-existing human stem cell lines and rapid OPC programming protocols to evaluate the maturation of human DS-derived OPCs for the first time. Next, in a series of in vitro experiments, we will test two FDA-approved drugs for their ability to prompt OPC differentiation and then test their myelination potential by transplanting these cells into the myelin-deficient Shiverer mouse brain. The results of these studies will generate a novel cellular resource for future study in the DS field, test the hypothesis that human DS-derived OPCs exhibit the same defects found in mouse model cells, and evaluate the efficacy of two potential drugs that could be used to improve myelination in the brains of people with DS.

Public Health Relevance

The formation of white matter in the brains of people with Down syndrome (DS) is altered; evidence from mouse models indicates that this is due to deficits in the maturation of oligodendrocyte cells from birth to adulthood. One of our overall goals, therefore, is to improve the development of white matter in DS by applying drugs that promote oligodendrocyte growth. This project will test whether stem cell-derived human oligodendrocytes acquired from people with DS have the same defects found in the mouse model cells; we will also test whether two FDA-approved drugs can improve oligodendrocyte development and myelination.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Neurogenesis and Cell Fate Study Section (NCF)
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Parisi, Melissa
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Boston University
Anatomy/Cell Biology
Schools of Medicine
United States
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