Molecular cartography of the human down syndrome and trisomic mouse brain.

Down syndrome (DS, or Trisomy 21) is one of the most common genetic causes of intellectual disability. DS results in both abnormal neurodevelopment and accelerated neurodegeneration, but the molecular mechanisms underlying abnormal corticogenesis are incompletely understood. To gain molecular insight into the prenatal neurobiology of DS, we performed single-nucleus sequencing, spatial transcriptomics, and proteomics on mid-gestational prenatal human cortex. We captured altered expression dynamics of lineage commitment genes and de-repression of transposable elements in DS neural progenitor cells, which suggest changes to the fate and functionality of neuronal and glial cells. Given the importance of linking human and model system pathobiology, we also performed highly multiplexed RNA in situ spatial transcriptomics on a well-established trisomic mouse model (Ts65Dn) to study the cellular landscape of the trisomic brain during early development and maturation. We profiled the spatial transcriptome of > 240,000 cells in the mouse brain and identified trisomy-associated gene expression patterns in the molecular control of neurogenesis and gliogenesis. Together, our study provides an extensive resource for understanding of the complex multicellular processes underlying DS neurodevelopment.