The appearance of cognitive deficits and altered brain morphology in newborns with Down syndrome (DS) suggests that these features are driven by disruptions at the earliest stages of brain development. Despite its high prevalence and extensively characterized cognitive phenotypes, relatively little is known about the cellular and molecular mechanisms that drive the changes seen in DS. Recent technical advances, such as single-cell omics and the development of induced pluripotent stem cell (iPSC) models of DS, now enable in-depth analyses of the biochemical and molecular drivers of altered brain development in DS. Here, we review the current state of knowledge on brain development in DS, focusing primarily on data from human post-mortem brain tissue. We explore the biological mechanisms that have been proposed to lead to intellectual disability in DS, assess the extent to which data from studies using iPSC models supports these hypotheses, and identify current gaps in the field.

患有唐氏综合症 （DS） 的新生儿出现认知缺陷和大脑形态改变表明，这些特征是由大脑发育早期的中断驱动的。尽管其患病率高且具有广泛的认知表型特征，但对驱动 DS 中变化的细胞和分子机制知之甚少。最近的技术进展，如单细胞组学和 DS 诱导多能干细胞 （iPSC） 模型的开发，现在可以深入分析 DS 大脑发育改变的生化和分子驱动因素。在这里，我们回顾了 DS 大脑发育的现状，主要关注来自人类死后脑组织的数据。我们探讨了导致 DS 智力障碍的生物学机制，评估使用 iPSC 模型的研究数据支持这些假设的程度，并确定该领域的当前差距。