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Dysfunctional synaptic pruning by microglia correlates with cognitive impairment in sleep-deprived mice: Involvement
Lu Wang1,2, Hanyi Ling2, Hui He2
1The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, 610054, China.
Abstract:
Microglia are involved in sleep/wake cycles and the response to sleep loss. Synaptic pruning by microglia is necessary for central nervous system circuit refinement and contributes to cognitive function. Here, we investigated whether and how microglia-mediated synaptic pruning may be involved in cognitive deficits induced by sleep deprivation in mice. Mice were deprived of sleep by leaving them in a spontaneously rotating rod for 72 h, after which their cognitive function was assessed using an object location test, Y maze, and novel object recognition test. Sleep deprivation lowered the discrimination index for familiar locations in the object location test and Y maze. Microglial morphology was assessed using immunostaining Iba1, while microglia-mediated synaptic pruning was examined based on immunostaining PSD95, CD68, and Iba1. Sleep deprivation also activated microglial cells in the hippocampus, as reflected in bigger soma as well as fewer and shorter branches than normal sleep. Sleep deprivation downregulated phagocytic markers and internalization of postsynaptic protein 95 (PSD95), suggesting impaired synaptic pruning. CX3C motif chemokine receptor 1 (CX3CR1) signaling was detected in in vitro experiments. Sleep deprivation also downregulated CX3CR1. Activation of CX3CR1 signaling increased phagocytosis activity of BV2 microglia in vitro. Sleep deprivation dysregulates microglial CX3CR1 signaling and inhibits synaptic pruning, contributing to associated cognitive deficits. These findings identify CX3CR1-dependent synaptic pruning as a potential therapeutic target in which sleep deprivation causes recognition impairments.
Insights
Sleep deprivation impairs cognitive function by disrupting microglial synaptic pruning. This involves dysregulation of CX3C motif chemokine receptor 1 (CX3CR1) signaling, highlighting it as a therapeutic target.
Area of Science:
- Neuroscience
- Cell Biology
- Sleep Research
Background:
- Microglia play a crucial role in synaptic pruning, essential for cognitive function.
- Sleep deprivation is known to induce cognitive deficits, but the underlying mechanisms involving microglia are not fully understood.
Purpose of the Study:
- To investigate the role of microglia-mediated synaptic pruning in cognitive deficits caused by sleep deprivation in mice.
- To examine the involvement of CX3C motif chemokine receptor 1 (CX3CR1) signaling in this process.
Main Methods:
- Mice underwent 72 hours of sleep deprivation.
- Cognitive function was assessed using object location, Y maze, and novel object recognition tests.
- Microglial morphology and synaptic pruning were analyzed via immunostaining (Iba1, PSD95, CD68); CX3CR1 signaling was studied in vitro.
Main Results:
- Sleep deprivation impaired cognitive performance and altered microglial morphology in the hippocampus.
- Synaptic pruning was inhibited, evidenced by downregulated phagocytic markers and reduced PSD95 internalization.
- Sleep deprivation downregulated CX3CR1, while its activation enhanced microglial phagocytosis in vitro.
Conclusions:
- Sleep deprivation dysregulates microglial CX3CR1 signaling, inhibiting synaptic pruning and contributing to cognitive impairments.
- CX3CR1-dependent synaptic pruning is a potential therapeutic target for sleep deprivation-induced recognition deficits.
