Quetiapine promotes oligodendroglial process outgrowth and membrane expansion by orchestrating the effects of Olig1

• Published in: Glia Vol. 69; no. 7; pp. 1709 - 1722
• Main Authors: Wang, Xiaorui, Su, Yixun, Li, Tao, Yu, Guangdan, Wang, Yuxin, Chen, Xiaoying, Yin, Chenrui, Tang, Ziqin, Yi, Chenju, Xiao, Lan, Niu, Jianqin
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.07.2021; Wiley Subscription Services, Inc
• Subjects: Antipsychotics; Axons - metabolism; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cell differentiation; Cell Differentiation - physiology; Cytosol; Differentiation; Genetic transformation; GPR17; Maturation; Membrane structures; Membranes; Morphology; Myelin; Myelin Sheath - metabolism; Myelination; Olig1; Oligodendrocytes; Oligodendroglia - metabolism; OPC differentiation; process outgrowth; Quetiapine; Quetiapine Fumarate - metabolism; Quetiapine Fumarate - pharmacology; Regulatory mechanisms (biology); Segments; Translocation; quetiapine; GPR17; process outgrowth; OPC differentiation; Olig1
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23986

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. Main Points QUE promotes morphological maturation of oligodendroglia in vivo and in vitro. QUE upregulates Olig1 expression level and prompts its nuclear–cytoplasmic translocation. QUE prevents over‐expressed GPR17 from negatively regulating oligodendroglial morphological maturation.