title: Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling.
abstract: Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders.
authors.affiliation: Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.|University of the Basque Country, Leioa, Spain.
authors.forename: Oihane
authors.identifier: 0000-0002-5428-7823
authors.initials: O
authors.lastname: Abiega
authors.affiliation: Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.|University of the Basque Country, Leioa, Spain.
authors.forename: Sol
authors.identifier: 0000-0003-3959-462X
authors.initials: S
authors.lastname: Beccari
authors.affiliation: Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.|University of the Basque Country, Leioa, Spain.
authors.forename: Irune
authors.identifier: 0000-0003-0048-9005
authors.initials: I
authors.lastname: Diaz-Aparicio
authors.affiliation: Université Bordeaux Segalen, Bordeaux, France.
authors.forename: Agnes
authors.initials: A
authors.lastname: Nadjar
authors.affiliation: Université Bordeaux Segalen, Bordeaux, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Layé
authors.affiliation: Université Bordeaux Segalen, Bordeaux, France.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Leyrolle
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Diego
authors.initials: D
authors.lastname: Gómez-Nicola
authors.affiliation: Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.|University of the Basque Country, Leioa, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Domercq
authors.affiliation: Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.|University of the Basque Country, Leioa, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Pérez-Samartín
authors.affiliation: Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.|University of the Basque Country, Leioa, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Sánchez-Zafra
authors.affiliation: Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.|University of the Basque Country, Leioa, Spain.
authors.forename: Iñaki
authors.identifier: 0000-0002-3887-0277
authors.initials: I
authors.lastname: Paris
authors.affiliation: Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.|University of the Basque Country, Leioa, Spain.|Ikerbasque Foundation, Bilbao, Spain.
authors.forename: Jorge
authors.identifier: 0000-0001-6072-3313
authors.initials: J
authors.lastname: Valero
authors.affiliation: Centre de recherche du CHU de Québec, Axe Neurosciences, Québec, Canada.|Université Laval, Département de médecine moléculaire, Québec, Canada.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Savage
authors.affiliation: Centre de recherche du CHU de Québec, Axe Neurosciences, Québec, Canada.|Université Laval, Département de médecine moléculaire, Québec, Canada.
authors.forename: Chin-Wai
authors.initials: CW
authors.lastname: Hui
authors.affiliation: Centre de recherche du CHU de Québec, Axe Neurosciences, Québec, Canada.|Université Laval, Département de médecine moléculaire, Québec, Canada.
authors.forename: Marie-Ève
authors.identifier: 0000-0003-2863-9626
authors.initials: MÈ
authors.lastname: Tremblay
authors.affiliation: Baylor College of Medicine, The Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, United States of America.
authors.forename: Juan J P
authors.initials: JJ
authors.lastname: Deudero
authors.affiliation: Baylor College of Medicine, The Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, United States of America.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Brewster
authors.affiliation: Baylor College of Medicine, The Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, United States of America.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Anderson
authors.affiliation: University Hospital of Cruces, Bilbao, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Zaldumbide
authors.affiliation: University Hospital of Cruces, Bilbao, Spain.
authors.forename: Lara
authors.initials: L
authors.lastname: Galbarriatu
authors.affiliation: University Hospital of Cruces, Bilbao, Spain.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Marinas
authors.affiliation: CIC BioGUNE, Derio, Spain.
authors.forename: Maria dM
authors.initials: Md
authors.lastname: Vivanco
authors.affiliation: Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.|University of the Basque Country, Leioa, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Matute
authors.affiliation: Centre de recherche du CHU de Québec, Axe Neurosciences, Québec, Canada.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Maletic-Savatic
authors.affiliation: Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.|University of the Basque Country, Leioa, Spain.|Baylor College of Medicine, The Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, United States of America.
authors.forename: Juan M
authors.identifier: 0000-0002-0402-972X
authors.initials: JM
authors.lastname: Encinas
authors.affiliation: Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.|University of the Basque Country, Leioa, Spain.|Baylor College of Medicine, The Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, United States of America.
authors.forename: Amanda
authors.identifier: 0000-0001-8415-096X
authors.initials: A
authors.lastname: Sierra
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D000073883:CX3C Chemokine Receptor 1; D004833:Epilepsy, Temporal Lobe / Q000503:physiopathology*; D006801:Humans; D007608:Kainic Acid / Q000633:toxicity; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D009000:Monocytes / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010587:Phagocytosis / Q000502:physiology*; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology
chemical_list: D000073883:CX3C Chemokine Receptor 1; C515335:Ccr2 protein, mouse; C471885:Cx3cr1 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D000255:Adenosine Triphosphate; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse; D007608:Kainic Acid