Leal-Campanario, Rocio, Alarcon-Martinez, Luis, Rieiro, Hector, Martinez-Conde, Susana, Alarcon-Martinez, Tugba, Zhao, Xiuli, LaMee, Jonathan, Popp, Pamela J Osborn, Calhoun, Michael E, Arribas, Juan I, Schlegel, Alexander A, Stasi, Leandro L Di, Rho, Jong M, Inge, Landon, Otero-Millan, Jorge, Treiman, David M, and Macknik, Stephen L
Seizure-driven brain damage in epilepsy accumulates over time, especially in the hippocampus, which can lead to sclerosis, cognitive decline, and death. Excitotoxicity is the prevalent model to explain ictal neurodegeneration. Current labeling technologies cannot distinguish between excitotoxicity and hypoxia, however, because they share common molecular mechanisms. This leaves open the possibility that undetected ischemic hypoxia, due to ictal blood flow restriction, could contribute to neurodegeneration previously ascribed to excitotoxicity. We tested this possibility with Confocal Laser Endomicroscopy (CLE) and novel stereological analyses in several models of epileptic mice. We found a higher number and magnitude of NG2+ mural-cell mediated capillary constrictions in the hippocampus of epileptic mice than in that of normal mice, in addition to spatial coupling between capillary constrictions and oxidative stressed neurons and neurodegeneration. These results reveal a role for hypoxia driven by capillary blood flow restriction in ictal neurodegeneration.