Mid-gestational cell-type-specific transcriptomic signatures in the prefrontal and superior temporal cortex in Down syndrome

The cellular and molecular mechanisms underlying cortical alterations during early fetal development in Down syndrome (DS) remain largely unexplored. Here, we perform single-nucleus RNA sequencing (snRNA-seq) analysis on mid-gestational DS and control brain samples, including prefrontal cortex (PFC) and superior temporal plane cortex (STP). Through comparative spatiotemporal analyses, we decode cell-type- and region-specific transcriptional alterations associated with chr21 abnormalities, including a disrupted inhibitory-to-excitatory balance during mid-gestational development. RUNX1 and APP emerge as the most significantly dysregulated chromosome21 genes in the PFC and STP, respectively. Abnormal cortical distribution of excitatory neurons in both regions is potentially driven by dysregulated neuronal migration genes and impaired lactylation metabolism. Moreover, glial cells modulate the differentiation and migration of excitatory neurons through multiple intercellular signaling pathways. These findings provide critical insights into the pathogenesis of DS-related mid-gestational cortical abnormalities and offer valuable resources for disease modeling and development of spatiotemporally targeted therapeutic strategies.