Abstract
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.
Highlights
One obstacle to determining the relative contributions of excitotoxicity and hypoxia to neurodegeneration has been that, whereas the effects of excitotoxicity can be tested in vitro, hypoxia due to microvascular ischemia can only be tested in vivo
In the awake KO and KA cohorts we performed in vivo mural cell imaging of vasospasms, novel stereological methods, and cortical two-photon imaging of mural cell vasospasms to determine the effects of abnormal blood flow on ictal cell death
We found that ictal neurodegeneration is spatially associated with the microvasculature, which supports the presence of ischemia-related sources of neural degeneration in epilepsy
Summary
One obstacle to determining the relative contributions of excitotoxicity and hypoxia to neurodegeneration has been that, whereas the effects of excitotoxicity can be tested in vitro, hypoxia due to microvascular ischemia can only be tested in vivo. In vitro and in vivo cortical imaging has shown pericyte-driven capillary constrictions as a function of both drug application and functional local neural activity in healthy animals. Intravenous mural cell labeling and in vivo imaging showed that mural cells drove the capillary constrictions in both epileptic and healthy animals. We found that apoptotic neurons in epileptic animals were more closely associated to the microvasculature than non-apoptotic cells, and that the apoptotic cells that were found in healthy animals were not associated with the vasculature. These results reveal a contribution of ischemic hypoxia to ictal neurodegeneration
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