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CX3CL1/CX3CR1 signal mediates M1-type microglia and accelerates high-altitude-induced forgetting
Xueting Wang1, Yuqi Xie1, Yun Niu1
1Institute of Special Environmental Medicine, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.
Introduction:
Hypoxia-induced neuronal damage is the primary cause of cognitive impairment induced by high-altitude exposure. Microglia play a crucial regulatory role in the central nervous system (CNS) homeostasis and synaptic plasticity. M1-type polarized microglia are suspected to be responsible for CNS injury under hypoxic conditions, but the exact molecular mechanism is still unelucidated.
Methods:
CX3CR1 knock out and wide type mice were exposed to a simulated plateau at 7000 m for 48 h to construct the model of hypobaric hypoxia-induced memory impairment. The memory impairment of mice was assessed by Morris water maze. The dendritic spine density in the hippocampus was examined by Golgi staining. The synapses in the CA1 region and the number of neurons in the DG region were examined by immunofluorescence staining. The synapses in microglia activation and phagocytosis were examined by immunofluorescence. The levels of CX3CL1/CX3CR1 and their downstream proteins were detected. CX3CR1 knockout primary microglia were treated with CX3CL1 combined with 1% O2. The levels of proteins related to microglial polarization, the uptake of synaptosome and phagocytotic ability of microglia were detected.
Results:
In this study, mice exposed to a simulated 7000 m altitude for 48 h developed significant amnesia for recent memories, but no significant change in their anxiety levels was observed. Hypobaric hypoxia exposure (7000 m altitude above sea level for 48 h) resulted in synapse loss in the CA1 region of the hippocampus, but no significant changes occurred in the total number of neurons. Meanwhile, microglia activation, increased phagocytosis of synapses by microglia, and CX3CL1/CX3CR1 signal activation were observed under hypobaric hypoxic exposure. Further, we found that after hypobaric hypoxia exposure, CX3CR1-deficient mice showed less amnesia, less synaptic loss in the CA1 region, and less increase in M1 microglia, compared to their wildtype siblings. CX3CR1-deficient microglia did not exhibit M1-type polarization in response to either hypoxia or CX3CL1 induction. Both hypoxia and CX3CL1 induced the phagocytosis of synapses by microglia through the upregulation of microglial phagocytosis.
Discussion:
The current study demonstrates that CX3CL1/CX3CR1 signal mediates the M1-type polarization of microglia under high-altitude exposure and upregulates microglial phagocytosis, which increases the phagocytosis of synapses in the CA1 region of the hippocampus, causing synaptic loss and inducing forgetting.
Insights
High-altitude exposure causes memory loss by activating microglia, which engulf synapses. Blocking the CX3CL1/CX3CR1 pathway in mice reduced this damage, protecting against cognitive impairment.
Area of Science:
- Neuroscience
- Altitude Physiology
Background:
- Hypoxia from high altitude impairs cognition.
- Microglia, immune cells in the brain, are implicated in this neuronal damage.
- The precise mechanism of M1-polarized microglia in hypoxia-induced injury is unclear.
Purpose of the Study:
- Investigate the role of the CX3CL1/CX3CR1 signaling pathway in hypoxia-induced cognitive impairment.
- Elucidate the mechanism by which microglia contribute to synaptic loss under hypobaric hypoxia.
Main Methods:
- Mice were exposed to simulated high altitude (7000 m) to induce hypobaric hypoxia.
- Behavioral tests (Morris water maze) assessed memory impairment.
- Hippocampal synapse density, neuronal numbers, and microglial activation/phagocytosis were analyzed.
- CX3CL1/CX3CR1 signaling and downstream effects were quantified in wild-type and CX3CR1-knockout mice and primary microglia.
Main Results:
- Hypobaric hypoxia induced amnesia and synapse loss in the hippocampus (CA1 region) without affecting neuron numbers.
- Microglia showed activation and increased phagocytosis of synapses, correlating with CX3CL1/CX3CR1 pathway activation.
- CX3CR1-deficient mice exhibited reduced amnesia, less synaptic loss, and decreased M1 microglia polarization compared to controls.
- Hypoxia and CX3CL1 upregulated microglial phagocytosis, leading to synapse engulfment.
Conclusions:
- The CX3CL1/CX3CR1 pathway mediates M1 microglia polarization and enhances synaptic phagocytosis under high-altitude exposure.
- This process contributes to hippocampal synaptic loss and memory impairment.
- Targeting the CX3CL1/CX3CR1 pathway may offer a therapeutic strategy against high-altitude cognitive deficits.
