Dysfunctional S1P/S1PR1 signaling in the dentate gyrus drives vulnerability of chronic pain-related memory impairment.

IF 6.4 1区 生物学 Q1 BIOLOGY
eLife Pub Date : 2024-12-19 DOI:10.7554/eLife.99862
Mengqiao Cui, Xiaoyuan Pan, Zhijie Fan, Shulin Wu, Ran Ji, Xianlei Wang, Xiangxi Kong, Zhou Wu, Lingzhen Song, Weiyi Song, Jun-Xia Yang, Hongjie Zhang, Hongxing Zhang, Hai-Lei Ding, Jun-Li Cao
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引用次数: 0

Abstract

Memory impairment in chronic pain patients is substantial and common, and few therapeutic strategies are available. Chronic pain-related memory impairment has susceptible and unsusceptible features. Therefore, exploring the underlying mechanisms of its vulnerability is essential for developing effective treatments. Here, combining two spatial memory tests (Y-maze test and Morris water maze), we segregated chronic pain mice into memory impairment-susceptible and -unsusceptible subpopulations in a chronic neuropathic pain model induced by chronic constrictive injury of the sciatic nerve. RNA-Seq analysis and gain/loss-of-function study revealed that S1P/S1PR1 signaling is a determinant for vulnerability to chronic pain-related memory impairment. Knockdown of the S1PR1 in the dentate gyrus (DG) promoted a susceptible phenotype and led to structural plasticity changes of reduced excitatory synapse formation and abnormal spine morphology as observed in susceptible mice, while overexpression of the S1PR1 and pharmacological administration of S1PR1 agonist in the DG promoted an unsusceptible phenotype and prevented the occurrence of memory impairment, and rescued the morphological abnormality. Finally, the Gene Ontology (GO) enrichment analysis and biochemical evidence indicated that downregulation of S1PR1 in susceptible mice may impair DG structural plasticity via interaction with actin cytoskeleton rearrangement-related signaling pathways including Itga2 and its downstream Rac1/Cdc42 signaling and Arp2/3 cascade. These results reveal a novel mechanism and provide a promising preventive and therapeutic molecular target for vulnerability to chronic pain-related memory impairment.

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来源期刊
eLife
eLife BIOLOGY-
CiteScore
12.90
自引率
3.90%
发文量
3122
审稿时长
17 weeks
期刊介绍: eLife is a distinguished, not-for-profit, peer-reviewed open access scientific journal that specializes in the fields of biomedical and life sciences. eLife is known for its selective publication process, which includes a variety of article types such as: Research Articles: Detailed reports of original research findings. Short Reports: Concise presentations of significant findings that do not warrant a full-length research article. Tools and Resources: Descriptions of new tools, technologies, or resources that facilitate scientific research. Research Advances: Brief reports on significant scientific advancements that have immediate implications for the field. Scientific Correspondence: Short communications that comment on or provide additional information related to published articles. Review Articles: Comprehensive overviews of a specific topic or field within the life sciences.
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