Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling

• DOI: 10.1371/journal.pbio.1002466
• Publication Date: 2016-05-26T17:52:43Z
• Authors: Oihane Abiega; Sol Beccari; Irune Diaz-Aparicio; Agnes Nadjar; Sophie Layé; Quentin Leyrolle; Diego Gómez-Nicola; María Domercq; Alberto Pérez-Sam...; Víctor Sánchez-Zafra; Iñaki Paris; Jorge Valero; Julie C. Savage; Chin-Wai Hui; Marie-Ève Tremblay; Juan J. P. Deudero; Amy L. Brewster; Anne E. Anderson; Laura Zaldumbide; Lara Galbarriatu; Ainhoa Marinas; Maria dM. Vivanco; Carlos Matute; Mirjana Maletic-S...; Juan M. Encinas; Amanda Sierra
• Keywords: Excitotoxicity; Proinflammatory cytokine

Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role the diseased brain poorly explored. Recent findings suggest that adult hippocampal neurogenic niche, where excess newborn cells undergo apoptosis physiological conditions, phagocytosis efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes as well, we confronted them with series apoptotic challenges discovered generalized response. When challenged excitotoxicity vitro (via glutamate agonist NMDA) or inflammation vivo systemic administration bacterial lipopolysaccharides omega 3 fatty acid deficient diets), resorted different strategies boost their phagocytic efficiency compensate for increased cells, thus maintaining tightly coupled. Unexpectedly, this coupling was chronically lost mouse model mesial temporal lobe epilepsy (MTLE) well resected from individuals MTLE, major neurological disorder characterized seizures, excitotoxicity, inflammation. Importantly, loss phagocytosis/apoptosis correlated expression microglial proinflammatory, epileptogenic cytokines, suggesting contribution pathophysiology epilepsy. The blockade resulted reduced surveillance cell recognition receptor not directly mediated signaling through receptors. Instead, it related disruption local ATP microgradients caused hyperactivity network, at least acute phase Finally, uncoupling led an accumulation niche due decreased survival delayed clearance after seizures. These results demonstrate critically affects dynamics urge routinely assess neurodegenerative disorders.