Microglia modulate hippocampal synaptic transmission and sleep duration along the light/dark cycle

Corsi, Giorgio; Picard, Katherine; Castro, Maria Amalia Di; Garofalo, Stefano; Tucci, Federico; Chece, Giuseppina; Percio, Claudio Del; Golia, M; Raspa, Marcello; Scavizzi, Ferdinando; Decoeur, Fanny; Lauro, Clotilde; Rigamonti, Mara; Iannello, Fabio; Ragozzino, Davide; Russo, Eleonora; Bernardini, Giovanni; Nadjar, Agnès; Tremblay, Marie‐Ève; Babiloni, Claudio; Maggi, Laura; Limatola, Cristina

doi:10.1002/glia.24090

Cited by 60 publications

(61 citation statements)

References 85 publications

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“…Importantly, this work is the first to show canonical cycling genes maintain their diurnal expression patterns in the absence of microglia, suggesting microglia may not be key regulators of rhythmicity in the brain. These findings are consistent with a recent study showing no overt variations in diurnal and circadian motor activity patterns between control and PLX5622-treated mice 41 . Counter to this, a previous study concluded that microglial ablation disrupts the circadian system in Cx3cr1-diphtheria toxin rats 33 .…”

Section: Discussionsupporting

confidence: 93%

Cortical diurnal rhythms remain intact with microglial depletion

Barahona

Morabito

Swarup

et al. 2022

Sci Rep

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Microglia are subject to change in tandem with the endogenously generated biological oscillations known as our circadian rhythm. Studies have shown microglia harbor an intrinsic molecular clock which regulates diurnal changes in morphology and influences inflammatory responses. In the adult brain, microglia play an important role in the regulation of condensed extracellular matrix structures called perineuronal nets (PNNs), and it has been suggested that PNNs are also regulated in a circadian and diurnal manner. We sought to determine whether microglia mediate the diurnal regulation of PNNs via CSF1R inhibitor dependent microglial depletion in C57BL/6J mice, and how the absence of microglia might affect cortical diurnal gene expression rhythms. While we observe diurnal differences in microglial morphology, where microglia are most ramified at the onset of the dark phase, we do not find diurnal differences in PNN intensity. However, PNN intensity increases across many brain regions in the absence of microglia, supporting a role for microglia in the regulation of PNNs. Here, we also show that cortical diurnal gene expression rhythms are intact, with no cycling gene changes without microglia. These findings demonstrate a role for microglia in the maintenance of PNNs, but not in the maintenance of diurnal rhythms.

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Section: Discussionsupporting

confidence: 93%

Cortical diurnal rhythms remain intact with microglial depletion

Barahona

Morabito

Swarup

et al. 2022

Sci Rep

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“…Microglia contribute to downscaling during sleep by eliminating excitatory synapses (Choudhury et al, 2019), a behaviour presumably tuned down during wake by noradrenaline (Liu et al, 2019; Stowell et al, 2019). More recently, microglial CX3CR1 signalling was shown to differentially regulate excitatory synaptic transmission along the light/dark cycle (Corsi et al, 2021). We now show that microglia tune a sleep/wake regulation of inhibitory synapses restricted to cortical layer 1, via mobilization of the P2RX7/TNFα signalling and regulation of synaptic GABA A R content.…”

Section: Discussionmentioning

confidence: 99%

“…Many of the latter, such as prostaglandin, BDNF, IL- 1β or TNFα, control synaptic plasticity and were independently shown to regulate sleep (Porkka-Heiskanen, 2013). Recent work highlights the ability of microglia to control sleep duration (Corsi et al, 2021; Liu et al, 2021); however, whether and how microglia-released factors shape sleep via modulation of synaptic plasticity remains unknown.…”

mentioning

confidence: 99%

Microglial TNFα controls synaptic GABAARs, sleep slow waves and memory consolidation

Pinto

Bizien

Fabre

et al. 2022

Preprint

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Microglia sense the changes in their environment. How microglia actively translate these changes into suitable cues to adapt brain physiology is unknown. We reveal an activity-dependent regulation of cortical inhibitory synapses plasticity by microglia, driven by purinergic signaling acting on P2RX7 and mediated by microglia-derived TNFα. We demonstrate that sleep induces this microglia-dependent inhibitory plasticity by promoting synaptic enrichment of GABAARs. We further show that in turn, microglia-specific depletion of TNFα alters slow waves during NREM sleep and blunts sleep-dependent memory consolidation. Together, our results reveal that microglia orchestrate sleep-intrinsic plasticity of inhibitory synapses, ultimately sculpting sleep slow waves and memory.

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“…TNFα is a signaling molecule known to control activation of phosphorylation pathways (15)(16)(17). In the brain, TNFα is mostly if not exclusively produced by microglia (18,19), which are active sensors of brain state (20)(21)(22) and have been recently proposed to participate in the regulation of sleep (23)(24)(25). We therefore hypothesized that microglia-derived TNFα is involved in phosphorylation-based control of sleep.…”

Section: Introductionmentioning

confidence: 99%

Microglial TNFα orchestrates brain phosphorylation during the sleep period and controls homeostatic sleep

Pinto

Cottin

Dingli

et al. 2022

Preprint

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The time we spend asleep is adjusted to previous time spent awake, and therefore believed to be under tight homeostatic control. Here, we establish microglia as a new cellular component of the sleep homeostat circuit. By using quantitative phosphoproteomics we demonstrate that microglia-derived TNFα controls thousands of phosphorylation sites during the sleep period. Substrates of microglial TNFα comprise sleep-promoting kinases and numerous synaptic proteins, including a subset whose phosphorylation status codes sleep need and determines sleep duration. As a result, lack of microglial TNFα attenuates the build-up of sleep need, as measured by slow wave activity, and prevents immediate compensation for loss of sleep. Together, we propose that microglia control sleep homeostasis by releasing TNFα that acts at the neuronal circuitry through dynamic control of phosphorylation. attenuates the build-up of sleep need, as measured by slow wave activity, and prevents immediate compensation for loss of sleep. Together, we propose that microglia control sleep homeostasis by releasing TNFα that acts at the neuronal circuitry through dynamic control of phosphorylation.

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Microglia modulate hippocampal synaptic transmission and sleep duration along the light/dark cycle

Cited by 60 publications

References 85 publications

Cortical diurnal rhythms remain intact with microglial depletion

Cortical diurnal rhythms remain intact with microglial depletion

Microglial TNFα controls synaptic GABAARs, sleep slow waves and memory consolidation

Microglial TNFα orchestrates brain phosphorylation during the sleep period and controls homeostatic sleep

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