Dysfunctional S1P/S1PR1 signaling in the dentate gyrus drives vulnerability of chronic pain-related memory impairment
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 effec...
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eLife Sciences Publications Ltd
2024-12-01
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| Online Access: | https://elifesciences.org/articles/99862 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Mengqiao Cui |
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| description | 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. |
| format | Article |
| id | doaj-art-64f1f35c02284bd595c2c9509d7e4fe2 |
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| issn | 2050-084X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-64f1f35c02284bd595c2c9509d7e4fe22025-08-20T02:34:44ZengeLife Sciences Publications LtdeLife2050-084X2024-12-011310.7554/eLife.99862Dysfunctional S1P/S1PR1 signaling in the dentate gyrus drives vulnerability of chronic pain-related memory impairmentMengqiao Cui0https://orcid.org/0000-0002-7098-8718Xiaoyuan Pan1Zhijie Fan2Shulin Wu3Ran Ji4Xianlei Wang5Xiangxi Kong6Zhou Wu7https://orcid.org/0000-0002-1086-9290Lingzhen Song8Weiyi Song9Jun-Xia Yang10Hongjie Zhang11Hongxing Zhang12Hai-Lei Ding13Jun-Li Cao14https://orcid.org/0000-0002-8932-4743Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China; School of Public Health, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, ChinaFaculty of Health Sciences, University of Macau, Taipa, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China; Department of Anesthesiology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, ChinaMemory 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.https://elifesciences.org/articles/99862chronic painmemorydentate gyrussphingosine 1-phosphatesynaptic plasticity |
| spellingShingle | 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 Dysfunctional S1P/S1PR1 signaling in the dentate gyrus drives vulnerability of chronic pain-related memory impairment eLife chronic pain memory dentate gyrus sphingosine 1-phosphate synaptic plasticity |
| title | Dysfunctional S1P/S1PR1 signaling in the dentate gyrus drives vulnerability of chronic pain-related memory impairment |
| title_full | Dysfunctional S1P/S1PR1 signaling in the dentate gyrus drives vulnerability of chronic pain-related memory impairment |
| title_fullStr | Dysfunctional S1P/S1PR1 signaling in the dentate gyrus drives vulnerability of chronic pain-related memory impairment |
| title_full_unstemmed | Dysfunctional S1P/S1PR1 signaling in the dentate gyrus drives vulnerability of chronic pain-related memory impairment |
| title_short | Dysfunctional S1P/S1PR1 signaling in the dentate gyrus drives vulnerability of chronic pain-related memory impairment |
| title_sort | dysfunctional s1p s1pr1 signaling in the dentate gyrus drives vulnerability of chronic pain related memory impairment |
| topic | chronic pain memory dentate gyrus sphingosine 1-phosphate synaptic plasticity |
| url | https://elifesciences.org/articles/99862 |
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