Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination

Trisomy 21, or Down syndrome (DS), is the most common genetic cause of developmental delay and intellectual disability. To gain insight into the underlying molecular and cellular pathogenesis, we conducted a multi-region transcriptome analysis of DS and euploid control brains spanning from mid-fetal development to adulthood. We found genome-wide alterations in the expression of a large number of genes, many of which exhibited temporal and spatial specificity and were associated with distinct biological processes. In particular, we uncovered co-dysregulation of genes associated with oligodendrocyte differentiation and myelination that were validated via cross-species comparison to Ts65Dn trisomy mice. Furthermore, we show that hypomyelination present in Ts65Dn mice is in part due to cell-autonomous effects of trisomy on oligodendrocyte differentiation and results in slower neocortical action potential transmission. Together, these results identify defects in white matter development and function in DS, and they provide a transcriptional framework for further investigating DS neuropathogenesis. •Genome-wide spatiotemporal dysregulation of gene expression is found in DS brains•Transcriptome changes reflect altered oligodendrocyte development and myelination•Oligodendrocyte differentiation and myelination is altered in DS model mice (Ts65Dn)•Speed of action potential propagation is decreased in Ts65Dn neocortical white matter Olmos-Serrano et al. identify defects in oligodendrocyte differentiation and white matter development over the timespan in Down syndrome (DS) brain and in Ts65Dn trisomic mice. Their developmental gene expression study provides a new framework for investigating DS neuropathogenesis.