NORMENT Center of Excellence (CoE), Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Transl Psychiatry. 2021 Oct 29;11(1):554. doi: 10.1038/s41398-021-01681-4.
While neurodevelopmental abnormalities have been associated with schizophrenia (SCZ), the role of astroglia in disease pathophysiology remains poorly understood. In the present study, we used a human induced pluripotent stem cell (iPSC)-derived astrocyte model to investigate the temporal patterns of astroglia differentiation during developmental stages critical for SCZ using RNA sequencing. The model generated astrocyte-specific gene expression patterns during differentiation that corresponded well to astroglia-specific expression signatures of in vivo cortical fetal development. Using this model we identified SCZ-specific expression dynamics, and found that SCZ-associated differentially expressed genes were significantly enriched in the medial prefrontal cortex, striatum, and temporal lobe, targeting VWA5A and ADAMTS19. In addition, SCZ astrocytes displayed alterations in calcium signaling, and significantly decreased glutamate uptake and metalloproteinase activity relative to controls. These results implicate novel transcriptional dynamics in astrocyte differentiation in SCZ together with functional changes that are potentially important biological components of SCZ pathology.
虽然神经发育异常与精神分裂症（SCZ）有关，但星形胶质细胞在疾病病理生理学中的作用仍知之甚少。在本研究中，我们使用人类诱导多能干细胞（iPSC）衍生的星形胶质细胞模型，通过 RNA 测序研究了 SCZ 关键发育阶段星形胶质细胞分化的时间模式。该模型在分化过程中产生了星形胶质细胞特异性基因表达模式，与体内皮质胎儿发育的星形胶质细胞特异性表达特征非常吻合。使用该模型，我们确定了 SCZ 特异性表达动力学，并发现与 SCZ 相关的差异表达基因在中前额叶皮层、纹状体和颞叶中显著富集，靶向 VWA5A 和 ADAMTS19。此外，SCZ 星形胶质细胞的钙信号发生改变，与对照组相比，谷氨酸摄取和金属蛋白酶活性显著降低。这些结果表明，SCZ 中星形胶质细胞分化存在新的转录动力学，以及功能变化，这可能是 SCZ 病理学的重要生物学组成部分。
