GLUT1-mediated microglial proinflammatory activation contributes to the development of stress-induced spatial
Xue Wang1, Yuhan Wu1, Yingrui Tian1,2
1Beijing Institute of Basic Medical Sciences, Academy of Military Medical Sciences, #27 Taiping Road, Haidian, Beijing, 100850, China.
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.
Insights
Chronic stress causes cognitive decline by increasing hippocampal glucose and GLUT1 in microglia, leading to inflammation and memory loss. Targeting this pathway may treat stress-related memory disorders.
Area of Science:
- Neuroscience
- Metabolic pathways
- Neuroinflammation
Background:
- Stress is a known risk factor for cognitive decline.
- Neuroinflammation, involving microglial activation, is implicated in stress-induced cognitive impairment.
- The precise mechanisms linking stress, microglial activation, and memory deficits remain unclear.
Purpose of the Study:
- To investigate the role of hippocampal glucose metabolism and GLUT1 in microglial activation under chronic stress.
- To elucidate the impact of microglial GLUT1 on spatial learning and memory in a mouse model of chronic stress.
- To identify potential therapeutic targets for stress-related cognitive dysfunction.
Main Methods:
- Utilized a chronic stress mouse model to examine microglial activation and spatial memory.
- Assessed the effect of hippocampal hyperglycemia on microglial activation using glucose infusion and cell culture.
- Employed gain- and loss-of-function experiments, including AAV-mediated GLUT1 knockdown in microglia.
Main Results:
- Chronic stress induced microglial proinflammatory activation and neuroinflammation, correlating with spatial memory impairment.
- Elevated hippocampal glucose levels post-stress increased microglial GLUT1 expression, driving proinflammatory activation.
- Downregulation of microglial GLUT1 in stressed mice ameliorated neuroinflammation and memory deficits, involving the NF-κB pathway.
Conclusions:
- Elevated glucose and GLUT1 in microglia promote proinflammatory activation, contributing to stress-induced spatial memory dysfunction.
- This study reveals a critical link between metabolic changes and neuroinflammation in cognitive decline.
- Targeting the glucose-GLUT1-microglia axis offers a potential therapeutic strategy for stress-related memory disorders.
