title: Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress.
abstract: Chronic stress is one of the most relevant triggering factors for major depression. Microglial cells are highly sensitive to stress and, more generally, to environmental challenges. However, the role of these brain immune cells in mediating the effects of stress is still unclear. Fractalkine signaling - which comprises the chemokine CX3CL1, mainly expressed by neurons, and its receptor CX3CR1, almost exclusively present on microglia in the healthy brain - has been reported to critically regulate microglial activity. Here, we investigated whether interfering with microglial function by deleting the Cx3cr1 gene affects the brain's response to chronic stress. To this purpose, we housed Cx3cr1 knockout and wild-type adult mice in either control or stressful environments for 2weeks, and investigated the consequences on microglial phenotype and interactions with synapses, synaptic transmission, behavioral response and corticosterone levels. Our results show that hampering neuron-microglia communication via the CX3CR1-CX3CL1 pathway prevents the effects of chronic unpredictable stress on microglial function, short- and long-term neuronal plasticity and depressive-like behavior. Overall, the present findings suggest that microglia-regulated mechanisms may underlie the differential susceptibility to stress and consequently the vulnerability to diseases triggered by the experience of stressful events, such as major depression.
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Milior
authors.affiliation: Axe Neurosciences, Centre de recherche du CHU de Québec, 2705, boulevard Laurier, Québec, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lecours
authors.affiliation: Axe Neurosciences, Centre de recherche du CHU de Québec, 2705, boulevard Laurier, Québec, Canada.
authors.forename: Louis
authors.initials: L
authors.lastname: Samson
authors.affiliation: Axe Neurosciences, Centre de recherche du CHU de Québec, 2705, boulevard Laurier, Québec, Canada.
authors.forename: Kanchan
authors.initials: K
authors.lastname: Bisht
authors.affiliation: Section of Behavioural Neurosciences, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Poggini
authors.affiliation: Center for Life Nanoscience, Istituto Italiano di Tecnologia@Sapienza, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pagani
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy; Département de Neuroscience, Institut Pasteur, Unité Neurobiologie Intégrative des Systèmes Cholinergiques, Paris Cedex 15, Paris, France.
authors.forename: Cristina
authors.initials: C
authors.lastname: Deflorio
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lauro
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Alboni
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy; IRCCS Neuromed, Pozzilli, IS, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Limatola
authors.affiliation: Section of Behavioural Neurosciences, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Igor
authors.initials: I
authors.lastname: Branchi
authors.affiliation: Axe Neurosciences, Centre de recherche du CHU de Québec, 2705, boulevard Laurier, Québec, Canada. Electronic address: tremblay.marie-eve@crchudequebec.ulaval.ca.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Tremblay
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Maggi
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D000073883:CX3C Chemokine Receptor 1 / Q000172:deficiency*; D003865:Major Depressive Disorder / Q000503:physiopathology*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons; D015398:Signal Transduction / Q000502:physiology*; D013315:Stress, Psychological / Q000503:physiopathology*
chemical_list: D000073883:CX3C Chemokine Receptor 1
keywords: Chronic stress; Differential susceptibility; Environment; Fractalkine receptor; LTP; Life events; Major depression; Microglia; Phagocytosis; Plasticity