小儿阻塞性睡眠呼吸暂停模型中的胶质细胞功能障碍与记忆损伤

文献信息

中文摘要

小儿阻塞性睡眠呼吸暂停（POSA）是一种常见的儿童疾病，常导致大脑发育异常和认知缺陷。POSA中认知障碍的病理生理基础尚不清楚。在此，我们研究了具有学习和记忆缺陷的POSA小鼠模型中的细胞和分子病理学方面。我们对海马进行了单核RNA测序（snRNA-seq），以无偏倚和细胞类型特异性的方式检查基因表达变化。该数据集揭示了所有脑细胞类型中转录组的显著扰动，尤其是在胶质细胞和神经干细胞中。我们在蛋白质水平上验证了几个差异表达基因的表达降低：少突胶质细胞中的QDPR和SOX8，神经干细胞中的LRRK2和NDUFS4，小胶质细胞中的TFE3，以及星形胶质细胞中的GLUT1。将少突胶质细胞基因表达变化与蛋白质组数据集进行比较，提示髓鞘形成受损，我们在体内证实了这一点。此外，细胞水平分析显示海马中少突胶质细胞、星形胶质细胞和小胶质细胞的形态异常，以及颗粒下区神经干细胞数量减少。我们的研究确定了POSA中细胞和分子胶质细胞功能障碍，验证了用于进一步研究的基因靶点，并提供了一个snRNA-seq数据集以促进进一步的数据驱动假设生成。

英文摘要

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.