Abiega, O. 1 , Beccari, S. . 1 , Díaz-Aparicio, I. 1 , Encinas, J. M. 1, 2, 3 , Brewster, A. L. 4 , Anderson, A. 4 , Maletic-Savatic, M. 4 , Matute, C. 1, 2 & Sierra, A. 1, 2, 3
1 Achucarro Basque Center for Neuroscience, Zamudio, Spain
2 Department of Neuroscience, University of the Basque Country, Leioa, Spain
3 Ikerbasque, the Basque Foundation for Science, Bilbao, Spain
4 Neurological Research Institute, Baylor College of Medicine, Houston, Texas, USA
Phagocytosis is a highly conserved process essential to maintain tissue homeostasis, however little is known about its dynamics in the adult brain. Using as a model the adult neurogenic cascade, in which the majority of the newborn cells undergo apoptosis, we have established a series of parameters to quantify microglial phagocytosis dynamics. In physiological conditions, the apoptotic newborn cells are rapidly and efficiently phagocytosed by microglia. When subjected to phagocytic challenge in vivo (LPS-induced inflammation) or in organotypic slices (NMDA-induced excitotoxicity), microglia stand up to the increased apoptosis by raising proportionally their phagocytic capacity - hence, phagocytosis remains coupled to apoptosis. In contrast, microglial phagocytosis is strongly uncoupled from apoptosis in an in vivo model of epilepsy induced by kainate administration, leading to the accumulation of apoptotic cells and the development of an inflammatory response, providing the first in vivo evidence that phagocytosis and inflammation are inversely regulated. On the contrary, a lower dose of kainate induces interictal activity without inflammation and phagocytosis remains coupled to apoptosis. Therefore, our data shows that there is a neuronal hyperactivity threshold that has to be surpassed to trigger the phagocytic impairment. In fact, we provide evidence that microglia express low levels of glutamate receptors, which can mediate the microglial sensing of the surrounding neuronal activity. The mechanisms and consequences of phagocytosis blockade will be discussed.