Oligodendrocyte Enriched Brain Organoids Reveal Impaired Oligodendroglial Maturation and Altered Neural Network Activity in Down Syndrome

Abstract

Individuals with Down syndrome (DS) display developmental delay, intellectual disability, premature brain ageing, and an increased risk of Alzheimer-like neurodegeneration. Although the neuropathology of the postnatal and adult DS brain has been widely described, it remains unclear how trisomy 21 alters early human neural and glial development. Here, we used human oligodendrocyte enriched brain organoids derived from trisomic and euploid iPSCs to define the cellular, functional, and molecular consequences of trisomy 21 during early brain development. Trisomic organoids exhibited an early growth delay, reduced oligodendroglial specification, and impaired oligodendrocyte maturation, resulting in decreased myelination. These defects were accompanied by increased astroglial output and delayed neuronal maturation. At the functional level, trisomic organoids showed elevated spontaneous network activity, but failed to mount normal coordinated responses to pharmacological stimulation, consistent with abnormal neural circuit development. Bulk RNA sequencing revealed the strongest transcriptomic dysregulation occurs at early neural and glial specification. Together, these findings show that trisomy 21 disrupts early developmental stages and establish oligodendrocyte enriched brain organoids as a human model to investigate the developmental origins of white matter and network dysfunction in DS.