Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex.

Down syndrome is a genetic condition that causes intellectual disability and is characterized by early-onset delays in motor, cognitive, and language development. The molecular mechanisms underlying these neurodevelopmental impairments remain poorly understood. We used single-nucleus multiomic sequencing to simultaneously profile gene expression and chromatin accessibility in the Down syndrome prefrontal cortex during early postnatal development, a critical period for synaptogenesis, neural maturation, and developmental neuroimmune interactions. Our findings reveal widespread dysregulation of chromatin accessibility and gene expression, with deficits spanning metabolic and synaptic pathways, oligodendrocyte lineage progression, and a pronounced neuroinflammatory signature. We present a molecular atlas of Down syndrome neuropathology at a critical stage of brain development, highlighting convergent neurodevelopmental and neurodegenerative pathways and informing potential targeted therapies for Down syndrome–associated neuroinflammation. Editor's summary: Down syndrome (DS) is characterized by intellectual disabilities and delays in brain development. In a pair of manuscripts, cortical development in DS has been unveiled at the molecular level using single-nucleus multiomic sequencing. Analyzing the neocortex at midgestation, Vuong et al. identified alterations in the speed of development of specific populations of neurons, including commissural/callosal and deep layer projection neurons. The neurons produced also showed abnormal specification. Risgaard et al. profiled the prefrontal cortex of DS juvenile brains and reported widespread dysregulation of chromatin accessibility and gene expression in pathways involved in synapse development, metabolism, and neuroinflammation, among others. Combined, the results of these studies provide valuable insights into alterations in brain development in DS (see the Perspective by Haydar and Li). —Mattia Maroso INTRODUCTION: Down syndrome (DS) is the most prevalent chromosomal abnormality and arguably one of the most genetically complex multigene disorders affecting humans. The presence of a supernumerary chromosome 21 gives rise to a multisystem condition that substantially affects the cardiovascular, musculoskeletal, and nervous systems. Intellectual disability represents a defining clinical feature of DS, making it the leading genetic cause of intellectual disability worldwide. The cognitive phenotype of individuals with DS includes specific deficits in cognition, attention, working memory, motor development, and expressive language that begin in the first months of life and progress to have major consequences on long-term academic, occupational, and daily life outcomes. RATIONALE: Although several neuropathological and neuroimaging studies have reported structural and functional abnormalities in the brains of individuals with DS, the underlying cellular and molecular mechanisms underlying these alterations are yet to be elucidated. Therefore, it is crucial to understand how the increased dosage of chromosome 21, which encodes around 250 protein-coding genes, disrupts the developmental cellular complexity of the human brain. RESULTS: We performed single-nucleus multiomic RNA + ATAC (assay for transposase-accessible chromatin) sequencing of 220,956 cells from five pairs of age- and sex-matched DS and unaffected control dorsolateral prefrontal cortex (dlPFC), a cortical area central to higher-order cognition and working memory, during the early postnatal period (0 to 3 years)—a critical window of synaptogenesis, neuronal and glial maturation, and developmental neuroimmune interactions. Our study reveals global dysregulation of gene expression and chromatin accessibility in the DS dlPFC. This dysregulation extends beyond simple gene-dosage effects in chromosome 21 and involves complex interactions between transcription, gene regulatory networks, and the accessible chromatin landscape of discrete cell types. We uncovered profound disruption of metabolic and synaptic gene expression programs in both excitatory and inhibitory neurons, accompanied by shifts in cortical cell composition, including an increased proportion of upper-layer excitatory neurons in DS. We found significant impairment of oligodendrocyte lineage progression in DS, with depletion of the oligodendrocyte progenitor cell pool, as well as deficits in myelin-related transcription in mature oligodendrocytes, indicating that there are multiple developmental deficits in oligodendrocyte lineage cells that impair the proper myelination of axons. Notably, we observed a pronounced neuroinflammatory signature marked by microglial activation, astrocyte reactivity, and cytokine dysregulation. We identified this neuroinflammatory state to be driven by both intrinsic neuronal and glial transcriptional changes and non–cell-autonomous interactions among vascular, glial, immune, and neuronal cells. The coexistence of neurodevelopmental abnormalities with early neurodegenerative features supports a model in which these processes are mechanistically linked, potentially compounding cognitive and functional impairment from the earliest stages of life in DS. These findings shift the temporal onset of DS-associated neurodegenerative processes to the early postnatal period and underscore the necessity for biomarker development and therapeutic strategies targeting disease modification during this critical developmental window. CONCLUSION: This resource provides a detailed and cell type–specific molecular atlas of gene expression and chromatin accessibility in the DS brain, establishing a foundation for the development of targeted therapeutic interventions addressing both developmental and degenerative aspects of DS neuropathology. Molecular mechanisms disrupted in the early postnatal Down syndrome prefrontal cortex.: Schematic displaying the cell types and mechanisms underlying neuroinflammation, metabolic and synaptic deficits, and oligodendrocyte lineage progression and myelination. AP-1, activator protein 1; JAK/STAT, Janus kinase/signal transducers and activators of transcription; IL, interleukin; HSP, heat shock protein; TREM2, triggering receptor expressed on myeloid cells 2; CR3, complement receptor 3; MHC, major histocompatibility complex. [ABSTRACT FROM AUTHOR]