Astrocytes are the most abundant cell type in the human brain and are important regulators of several critical cellular functions, including synaptic transmission. Although astrocytes are known to play a central role in the etiology and pathophysiology of schizophrenia, little is known about their potential involvement in clinical response to the antipsychotic clozapine. Moreover, astrocytes display a remarkable degree of morphological diversity, but the potential contribution of astrocytic subtypes to disease biology and drug response has received little attention. Here, we used state-of-the-art human induced pluripotent stem cell (hiPSC) technology to derive a morphological subtype of astrocytes from healthy individuals and individuals with schizophrenia, including responders and nonresponders to clozapine. Using functional assays and transcriptional profiling, we identified a distinct gene expression signature highly specific to schizophrenia as shown by disease association analysis of more than 10 000 diseases. We further found reduced levels of both glutamate and the NMDA receptor coagonist d-serine in subtype astrocytes derived from schizophrenia patients, and that exposure to clozapine only rescued this deficiency in cells from clozapine responders, providing further evidence that d-serine in particular, and NMDA receptor-mediated glutamatergic neurotransmission in general, could play an important role in disease pathophysiology and clozapine action. Our study represents a first attempt to explore the potential contribution of astrocyte diversity to schizophrenia pathophysiology using a human cellular model. Our findings suggest that specialized subtypes of astrocytes could be important modulators of disease pathophysiology and clinical drug response, and warrant further investigations.

中文翻译：

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人类 iPSC 星形胶质细胞形态亚群的推导和分子表征揭示了精神分裂症和氯氮平反应中的潜在作用

星形胶质细胞是人脑中最丰富的细胞类型，是包括突触传递在内的几种关键细胞功能的重要调节剂。尽管已知星形胶质细胞在精神分裂症的病因学和病理生理学中发挥核心作用，但对其在抗精神病药物氯氮平的临床反应中的潜在参与知之甚少。此外，星形胶质细胞表现出显着程度的形态多样性，但星形胶质细胞亚型对疾病生物学和药物反应的潜在贡献很少受到关注。在这里，我们使用最先进的人类诱导多能干细胞 (hiPSC) 技术从健康个体和精神分裂症患者（包括对氯氮平的应答者和无应答者）中获得星形胶质细胞的形态亚型。使用功能测定和转录分析，我们确定了对精神分裂症高度特异性的独特基因表达特征，如对 10 000 多种疾病的疾病关联分析所示。我们进一步发现精神分裂症患者亚型星形胶质细胞中谷氨酸和 NMDA 受体激动剂 d-丝氨酸的水平降低，并且暴露于氯氮平只能挽救氯氮平反应者细胞中的这种缺陷，提供了进一步的证据，特别是 d-丝氨酸，和NMDA 受体介导的谷氨酸能神经传递通常在疾病的病理生理学和氯氮平作用中起重要作用。我们的研究首次尝试使用人类细胞模型探索星形胶质细胞多样性对精神分裂症病理生理学的潜在贡献。