Large extracellular space leads to neuronal susceptibility to ischemic injury in a Na+/K+ pumps-dependent manner.

The extent of anoxic depolarization (AD), the initial electrophysiological event during ischemia, determines the degree of brain region-specific neuronal damage. Neurons in higher brain regions exhibiting nonreversible, strong AD are more susceptible to ischemic injury as compared to cells in lower brain regions that exhibit reversible, weak AD. While the contrasting ADs in different brain regions in response to oxygen-glucose deprivation (OGD) is well established, the mechanism leading to such differences is not clear. Here we use computational modeling to elucidate the mechanism behind the brain region-specific recovery from AD. Our extended Hodgkin-Huxley (HH) framework consisting of neural spiking dynamics, processes of ion accumulation, and ion homeostatic mechanisms unveils that glial-vascular K(+) clearance and Na(+)/K(+)-exchange pumps are key to the cell's recovery from AD. Our phase space analysis reveals that the large extracellular space in the upper brain regions leads to impaired Na(+)/K(+)-exchange pumps so that they function at lower than normal capacity and are unable to bring the cell out of AD after oxygen and glucose is restored.