Abstract
Microglia, the brain's resident macrophages, actively contribute to the homeostasis of cerebral parenchyma by sensing neuronal activity and supporting synaptic remodeling and plasticity. While several studies demonstrated different roles for astrocytes in sleep, the contribution of microglia in the regulation of sleep/wake cycle and in the modulation of synaptic activity in the different day phases has not been deeply investigated. Using light as a zeitgeber cue, we studied the effects of microglial depletion with the colony stimulating factor‐1 receptor antagonist PLX5622 on the sleep/wake cycle and on hippocampal synaptic transmission in male mice. Our data demonstrate that almost complete microglial depletion increases the duration of NREM sleep and reduces the hippocampal excitatory neurotransmission. The fractalkine receptor CX3CR1 plays a relevant role in these effects, because cx3cr1 GFP/GFP mice recapitulate what found in PLX5622‐treated mice. Furthermore, during the light phase, microglia express lower levels of cx3cr1 and a reduction of cx3cr1 expression is also observed when cultured microglial cells are stimulated by ATP, a purinergic molecule released during sleep. Our findings suggest that microglia participate in the regulation of sleep, adapting their cx3cr1 expression in response to the light/dark phase, and modulating synaptic activity in a phase‐dependent manner.
Highlights
The environmental light changes caused by the 24-h period of Earth's rotation around its axis modulate the internal clock in our brain, triggering cycles of alertness and sleepiness in the circadian rhythm
We investigated the role of microglia in the changes associated to sleep/wake phases throughout the 12:12 light/dark cycle, focusing on the modulation of hippocampal synaptic functions and on behavioral states upon microglial depletion with colony stimulating factor-1 receptor (CSF-1R) inhibitor
We demonstrate for the first time that the microglial depletion with PLX5622 increases the time spent by mice in the non-rapid eye movement (NREM) sleep during the dark phase
Summary
The environmental light changes caused by the 24-h period of Earth's rotation around its axis modulate the internal clock in our brain, triggering cycles of alertness and sleepiness in the circadian rhythm. We treated mice with PLX5622, a CSF-1R inhibitor that drastically reduces the density of microglial cells in different brain regions, and we analyzed different endpoints: (1) the time spent in sleep or active states during the light and dark phases of the day; (2) the basal excitatory synaptic transmission; and (3) neuronal plasticity processes in the hippocampal region at ZT4 (light) and ZT16 (dark). These two time points were selected for being far from the light changes and better representing constant behavioral conditions. We demonstrated that under physiological conditions, microglia affect the duration of sleep and are necessary for synaptic changes occurring during the wake phase, disclosing a key role for CX3CR1 in sleep–wake cycle
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