Gene Enrichment Analysis of Astrocyte Subtypes in Psychiatric Disorders and Psychotropic Medication Datasets.
Gene Enrichment Analysis of Astrocyte Subtypes in Psychiatric Disorders and Psychotropic Medication Datasets.
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精神疾病和精神药物数据集中星形胶质细胞亚型的基因富集分析。
DOI：
10.3390/cells11203315
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发表时间：
2022-10-21
期刊：
影响因子：
6
通讯作者：
O'Donovan, Sinead M.
中科院分区：
文献类型：
--
作者：
Zhang, Xiaolu;Wolfinger, Alyssa;Wu, Xiaojun;Alnafisah, Rawan;Imami, Ali;Hamoud, Abdul-rizaq;Lundh, Anna;Parpura, Vladimir;McCullumsmith, Robert E.;Shukla, Rammohan;O'Donovan, Sinead M.
星形胶质细胞在大脑中具有许多重要功能，但它们在精神疾病中的作用及其对精神药物的反应仍在阐明中。在这里，我们使用基因富集分析来评估不同星形胶质细胞亚型、精神疾病和精神药物（抗精神病药、抗抑郁药和情绪稳定剂）之间的关系。我们还进行了 qPCR 分析和“查找”研究，以评估这些药物对星形胶质细胞标记基因表达的慢性影响。我们的生物信息分析确定了精神疾病中不同星形胶质细胞亚型的基因富集。在精神分裂症中发现了最高水平的富集，支持星形胶质细胞在这种疾病中的作用。我们还发现与特定生物过程相关的星形胶质细胞亚型的差异富集，突出了星形胶质细胞在病理条件下的复杂反应。通过生化分析证实了星形胶质细胞中蛋白质磷酸化的富集和疾病。对 LINCS 化学扰动基因特征的分析还发现，激酶抑制剂与星形胶质细胞-SCZ 相关基因特征高度不一致。然而，我们发现不同精神药物和星形胶质细胞亚型的共同基因富集是有限的。这些结果得到了“查找”研究和 qPCR 分析的证实，该分析还报告了精神药物对常见星形胶质细胞标记基因表达的影响很小，这表明星形胶质细胞不是这些药物的主要目标。相反，抗精神病药物确实会影响死后精神分裂症脑组织中星形胶质细胞基因标记的表达，支持不同病理条件下的特定星形胶质细胞反应。总体而言，这项研究提供了关于星形胶质细胞亚型以及药物对疾病中星形胶质细胞的影响的独特观点，这将有助于我们了解它们在精神疾病中的作用，并为治疗靶向星形胶质细胞提供见解。
Astrocytes have many important functions in the brain, but their roles in psychiatric disorders and their responses to psychotropic medications are still being elucidated. Here, we used gene enrichment analysis to assess the relationships between different astrocyte subtypes, psychiatric diseases, and psychotropic medications (antipsychotics, antidepressants and mood stabilizers). We also carried out qPCR analyses and “look-up” studies to assess the chronic effects of these drugs on astrocyte marker gene expression. Our bioinformatic analysis identified gene enrichment of different astrocyte subtypes in psychiatric disorders. The highest level of enrichment was found in schizophrenia, supporting a role for astrocytes in this disorder. We also found differential enrichment of astrocyte subtypes associated with specific biological processes, highlighting the complex responses of astrocytes under pathological conditions. Enrichment of protein phosphorylation in astrocytes and disease was confirmed by biochemical analysis. Analysis of LINCS chemical perturbagen gene signatures also found that kinase inhibitors were highly discordant with astrocyte-SCZ associated gene signatures. However, we found that common gene enrichment of different psychotropic medications and astrocyte subtypes was limited. These results were confirmed by “look-up” studies and qPCR analysis, which also reported little effect of psychotropic medications on common astrocyte marker gene expression, suggesting that astrocytes are not a primary target of these medications. Conversely, antipsychotic medication does affect astrocyte gene marker expression in postmortem schizophrenia brain tissue, supporting specific astrocyte responses in different pathological conditions. Overall, this study provides a unique view of astrocyte subtypes and the effect of medications on astrocytes in disease, which will contribute to our understanding of their role in psychiatric disorders and offers insights into targeting astrocytes therapeutically.
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