GLUT1-mediated microglial proinflammatory activation contributes to the development of stress-induced spatial learning and memory dysfunction in mice
Abstract Background Stress is a recognized risk factor for cognitive decline, which triggers neuroinflammation involving microglial activation. However, the specific mechanism for microglial activation under stress and affects learning and memory remains unclear. Methods The chronic stress mouse mod...
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Cell & Bioscience |
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| Online Access: | https://doi.org/10.1186/s13578-024-01229-1 |
| _version_ | 1797199104655228928 |
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| author | Xue Wang Yuhan Wu Yingrui Tian Hui Hu Yun Zhao Binghua Xue Zhaowei Sun Aijun Wei Fang Xie Ling-Jia Qian |
| author_facet | Xue Wang Yuhan Wu Yingrui Tian Hui Hu Yun Zhao Binghua Xue Zhaowei Sun Aijun Wei Fang Xie Ling-Jia Qian |
| author_sort | Xue Wang |
| collection | DOAJ |
| description | Abstract Background Stress is a recognized risk factor for cognitive decline, which triggers neuroinflammation involving microglial activation. However, the specific mechanism for microglial activation under stress and affects learning and memory remains unclear. Methods The chronic stress mouse model was utilized to explore the relationship between microglial activation and spatial memory impairment. The effect of hippocampal hyperglycemia on microglial activation was evaluated through hippocampal glucose-infusion and the incubation of BV2 cells with high glucose. The gain-and loss-of-function experiments were conducted to investigate the role of GLUT1 in microglial proinflammatory activation. An adeno-associated virus (AAV) was employed to specifically knockdown of GLUT1 in hippocampal microglia to assess its impact on stressed-mice. Results Herein, we found that chronic stress induced remarkable hippocampal microglial proinflammatory activation and neuroinflammation, which were involved in the development of stress-related spatial learning and memory impairment. Mechanistically, elevated hippocampal glucose level post-stress was revealed to be a key regulator of proinflammatory microglial activation via specifically increasing the expression of microglial GLUT1. GLUT1 overexpression promoted microglial proinflammatory phenotype while inhibiting GLUT1 function mitigated this effect under high glucose. Furthermore, specific downregulation of hippocampal microglial GLUT1 in stressed-mice relieved microglial proinflammatory activation, neuroinflammation, and spatial learning and memory injury. Finally, the NF-κB signaling pathway was demonstrated to be involved in the regulatory effect of GLUT1 on microglia. Conclusions We demonstrate that elevated glucose and GLUT1 expression induce microglia proinflammatory activation, contributing to stress-associated spatial memory dysfunction. These findings highlight significant interplay between metabolism and inflammation, presenting a possible therapeutic target for stress-related cognitive disorders. |
| first_indexed | 2024-04-24T07:10:27Z |
| format | Article |
| id | doaj.art-16f82017a1a1420697bd7bd219f07fbc |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-04-24T07:10:27Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-16f82017a1a1420697bd7bd219f07fbc2024-04-21T11:31:35ZengBMCCell & Bioscience2045-37012024-04-0114112110.1186/s13578-024-01229-1GLUT1-mediated microglial proinflammatory activation contributes to the development of stress-induced spatial learning and memory dysfunction in miceXue Wang0Yuhan Wu1Yingrui Tian2Hui Hu3Yun Zhao4Binghua Xue5Zhaowei Sun6Aijun Wei7Fang Xie8Ling-Jia Qian9Beijing Institute of Basic Medical Sciences, Academy of Military Medical SciencesBeijing Institute of Basic Medical Sciences, Academy of Military Medical SciencesBeijing Institute of Basic Medical Sciences, Academy of Military Medical SciencesBeijing Institute of Basic Medical Sciences, Academy of Military Medical SciencesBeijing Institute of Basic Medical Sciences, Academy of Military Medical SciencesBeijing Institute of Basic Medical Sciences, Academy of Military Medical SciencesBeijing Institute of Basic Medical Sciences, Academy of Military Medical SciencesBeijing Institute of Basic Medical Sciences, Academy of Military Medical SciencesBeijing Institute of Basic Medical Sciences, Academy of Military Medical SciencesBeijing Institute of Basic Medical Sciences, Academy of Military Medical SciencesAbstract Background Stress is a recognized risk factor for cognitive decline, which triggers neuroinflammation involving microglial activation. However, the specific mechanism for microglial activation under stress and affects learning and memory remains unclear. Methods The chronic stress mouse model was utilized to explore the relationship between microglial activation and spatial memory impairment. The effect of hippocampal hyperglycemia on microglial activation was evaluated through hippocampal glucose-infusion and the incubation of BV2 cells with high glucose. The gain-and loss-of-function experiments were conducted to investigate the role of GLUT1 in microglial proinflammatory activation. An adeno-associated virus (AAV) was employed to specifically knockdown of GLUT1 in hippocampal microglia to assess its impact on stressed-mice. Results Herein, we found that chronic stress induced remarkable hippocampal microglial proinflammatory activation and neuroinflammation, which were involved in the development of stress-related spatial learning and memory impairment. Mechanistically, elevated hippocampal glucose level post-stress was revealed to be a key regulator of proinflammatory microglial activation via specifically increasing the expression of microglial GLUT1. GLUT1 overexpression promoted microglial proinflammatory phenotype while inhibiting GLUT1 function mitigated this effect under high glucose. Furthermore, specific downregulation of hippocampal microglial GLUT1 in stressed-mice relieved microglial proinflammatory activation, neuroinflammation, and spatial learning and memory injury. Finally, the NF-κB signaling pathway was demonstrated to be involved in the regulatory effect of GLUT1 on microglia. Conclusions We demonstrate that elevated glucose and GLUT1 expression induce microglia proinflammatory activation, contributing to stress-associated spatial memory dysfunction. These findings highlight significant interplay between metabolism and inflammation, presenting a possible therapeutic target for stress-related cognitive disorders.https://doi.org/10.1186/s13578-024-01229-1Chronic stressMicrogliaProinflammatory activationGLUT1Spatial memory dysfunction |
| spellingShingle | Xue Wang Yuhan Wu Yingrui Tian Hui Hu Yun Zhao Binghua Xue Zhaowei Sun Aijun Wei Fang Xie Ling-Jia Qian GLUT1-mediated microglial proinflammatory activation contributes to the development of stress-induced spatial learning and memory dysfunction in mice Cell & Bioscience Chronic stress Microglia Proinflammatory activation GLUT1 Spatial memory dysfunction |
| title | GLUT1-mediated microglial proinflammatory activation contributes to the development of stress-induced spatial learning and memory dysfunction in mice |
| title_full | GLUT1-mediated microglial proinflammatory activation contributes to the development of stress-induced spatial learning and memory dysfunction in mice |
| title_fullStr | GLUT1-mediated microglial proinflammatory activation contributes to the development of stress-induced spatial learning and memory dysfunction in mice |
| title_full_unstemmed | GLUT1-mediated microglial proinflammatory activation contributes to the development of stress-induced spatial learning and memory dysfunction in mice |
| title_short | GLUT1-mediated microglial proinflammatory activation contributes to the development of stress-induced spatial learning and memory dysfunction in mice |
| title_sort | glut1 mediated microglial proinflammatory activation contributes to the development of stress induced spatial learning and memory dysfunction in mice |
| topic | Chronic stress Microglia Proinflammatory activation GLUT1 Spatial memory dysfunction |
| url | https://doi.org/10.1186/s13578-024-01229-1 |
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