Glial Dysfunction and Memory Impairments in a Model of Pediatric Obstructive Sleep Apnea

Pediatric obstructive sleep apnea (POSA) is a common childhood disease that often causes aberrant brain development and cognitive deficits. The pathophysiological underpinnings of cognitive impairments in POSA remain unclear. Here, we examined cellular and molecular aspects of pathology in a mouse model of POSA that features learning and memory deficits. We performed single-nucleus RNA-sequencing (snRNA-seq) of the hippocampus to examine gene expression changes in an unbiased and cell type-specific manner. This dataset revealed a striking perturbation of transcriptomes across all brain cell types, particularly within glia and neural stem cells. We validated reduced expression of several differentially expressed genes at protein level: QDPR and SOX8 in oligodendrocytes, LRRK2 and NDUFS4 in neural stem cells, TFE3 in microglia, and GLUT1 in astrocytes. Comparison of oligodendrocyte gene expression changes with proteomic datasets suggested impairments in myelination, which we confirmed in vivo. Furthermore, cellular level analyses demonstrated aberrant morphology of oligodendrocytes, astrocytes, and microglia in the hippocampus, and diminished numbers of neural stem cells in the subgranular zone. Our study identifies cellular and molecular glial cell dysfunction in POSA, validates gene targets for further study, and provides an snRNA-seq dataset to facilitate further data-driven hypothesis generation.