Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Brain and Intelligence Research Key Laboratory of Chongqing Education Commission, Third Military Medical University, Chongqing, China.
Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
Glia. 2021 Jul;69(7):1709-1722. doi: 10.1002/glia.23986. Epub 2021 Mar 4.
Oligodendroglial lineage cells go through a series of morphological changes before myelination. Prior to myelination, cell processes and membrane structures enlarge by approximately 7,000 times, which is required to support axonal wrapping and myelin segment formation. Failure of these processes leads to maldevelopment and impaired myelination. Quetiapine, an atypical antipsychotic drug, was proved to promote oligodendroglial differentiation and (re)myelination, pending detailed effects and regulatory mechanism. In this study, we showed that quetiapine promotes morphological maturation of oligodendroglial lineage cells and myelin segment formation, and a short-term quetiapine treatment is sufficient to induce these changes. To uncover the underlying mechanism, we examined the effect of quetiapine on the Oligodendrocyte transcription factor 1 (Olig1). We found that quetiapine upregulates Olig1 expression level and promotes nuclear Olig1 translocation to the cytosol, where it functions not as a transcription modulator, but in a way that highly correlates with oligodendrocyte morphological transformation. In addition, quetiapine treatment reverses the negative regulatory effect of the Olig1-regulated G protein-coupled receptor 17 (GPR17) on oligodendroglial morphological maturation. Our results demonstrate that quetiapine enhances oligodendroglial differentiation and myelination by promoting cell morphological transformation. This would shed light on the orchestration of oligodendroglia developmental mechanisms, and provides new targets for further therapeutic research.
少突胶质前体细胞在髓鞘形成前经历一系列形态变化。在髓鞘形成之前，细胞过程和膜结构增大约 7000 倍，这是支持轴突包裹和髓鞘节段形成所必需的。这些过程的失败会导致发育不良和髓鞘形成受损。喹硫平是一种非典型抗精神病药物，已被证明能促进少突胶质细胞分化和（再）髓鞘形成，但详细作用和调节机制尚不清楚。在这项研究中，我们表明喹硫平能促进少突胶质前体细胞的形态成熟和髓鞘节段形成，短期喹硫平处理足以诱导这些变化。为了揭示潜在的机制，我们研究了喹硫平对少突胶质细胞转录因子 1（Olig1）的影响。我们发现喹硫平上调 Olig1 的表达水平，并促进核 Olig1 易位到细胞质，在细胞质中，它不是作为转录调节剂，而是与少突胶质细胞形态转化高度相关。此外，喹硫平处理逆转了 Olig1 调节的 G 蛋白偶联受体 17（GPR17）对少突胶质细胞形态成熟的负调节作用。我们的结果表明，喹硫平通过促进细胞形态转化来增强少突胶质细胞分化和髓鞘形成。这将为少突胶质细胞发育机制的协调提供新的靶点，并为进一步的治疗研究提供新的靶点。
