Microglial homeostasis disruption modulates non-rapid eye movement sleep duration and neuronal activity in adult female mice

Katherine Picard, Giorgio Corsi, Fanny Decoeur, Maria Amalia Di Castro, Maude Bordeleau, Marine Persillet, Sophie Layé, Cristina Limatola, Marie-Ève Tremblay, Agnès Nadjar
Brain, Behavior, and Immunity. 2023-01-01; 107: 153-164
DOI: 10.1016/j.bbi.2022.09.016

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Picard K(1), Corsi G(2), Decoeur F(3), Di Castro MA(2), Bordeleau M(4), Persillet M(3), Layé S(3), Limatola C(5), Tremblay MÈ(6), Nadjar A(7).

Author information:
(1)Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval,
Québec, QC, Canada; Département de médecine moléculaire, Université Laval,
Québec, QC, Canada; Division of Medical Sciences, University of Victoria,
Victoria, BC, Canada.
(2)Department of Physiology and Pharmacology, Sapienza University of Rome, Rome,
Italy.
(3)Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000
Bordeaux, France.
(4)Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval,
Québec, QC, Canada; Division of Medical Sciences, University of Victoria,
Victoria, BC, Canada; Integrated Program in Neuroscience, McGill University,
Montreal, QC, Canada.
(5)Department of Physiology and Pharmacology, Sapienza University of Rome, Rome,
Italy; Department of Neurophysiology, Neuropharmacology, Inflammaging, IRCCS
Neuromed, Pozzilli, Italy.
(6)Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval,
Québec, QC, Canada; Département de médecine moléculaire, Université Laval,
Québec, QC, Canada; Division of Medical Sciences, University of Victoria,
Victoria, BC, Canada; Department of Biochemistry and Molecular Biology, The
University of British Columbia, Vancouver, BC, Canada; Department of Neurology
and Neurosurgery, McGill University, Montréal, QC, Canada; Centre for Advanced
Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC,
Canada. Electronic address: .
(7)Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000
Bordeaux, France; INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité
Neuronale, U1215, F-33000 Bordeaux, France; Institut Universitaire de France
(IUF), France. Electronic address: .

Sleep is a natural physiological state, tightly regulated through several
neuroanatomical and neurochemical systems, which is essential to maintain
physical and mental health. Recent studies revealed that the functions of
microglia, the resident immune cells of the brain, differ along the sleep-wake
cycle. Inflammatory cytokines, such as interleukin-1β and tumor necrosis
factor-α, mainly produced by microglia in the brain, are also well-known to
promote sleep. However, the contributing role of microglia on sleep regulation
remains largely elusive, even more so in females. Given the higher prevalence of
various sleep disorders in women, we aimed to determine the role of microglia in
regulating the sleep-wake cycle specifically in female mice. Microglia were
depleted in adult female mice with inhibitors of the colony-stimulating factor 1
receptor (CSF1R) (PLX3397 or PLX5622), which is required for microglial
population maintenance. This led to a 65-73% reduction of the microglial
population, as confirmed by immunofluorescence staining against IBA1 (marker of
microglia/macrophages) and TMEM119 (microglia-specific marker) in the reticular
nucleus of the thalamus and primary motor cortex. The spontaneous sleep-wake
cycle was evaluated at steady-state, during microglial homeostasis disruption and
after complete microglial repopulation, upon cessation of treatment with the
inhibitors of CSF1R, using electroencephalography (EEG) and electromyography
(EMG). We found that microglia-depleted female mice spent more time in non-rapid
eye movement (NREM) sleep and had an increased number of NREM sleep episodes,
which was partially restored after microglial total repopulation. To determine
whether microglia could regulate sleep locally by modulating synaptic
transmission, we used patch clamp to record spontaneous activity of pyramidal
neurons in the primary motor cortex, which showed an increase of excitatory
synaptic transmission during the dark phase. These changes in neuronal activity
were modulated by microglial depletion in a phase-dependent manner. Altogether,
our results indicate that microglia are involved in the sleep regulation of
female mice, further strengthening their potential implication in the development
and/or progression of sleep disorders. Furthermore, our findings indicate that
microglial repopulation can contribute to normalizing sleep alterations caused by
their partial depletion.

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