Potassium homeostasis in the ischemic brain

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Abstract
Extracellular [K+] can range within 2.5–3.5 mM under normal conditions to 50–80 mM under ischemic and spreading depression events. Sustained exposure to elevated [K+]o has been shown to cause significant neuronal death even under conditions of abundant glucose supply. Astrocytes are well equipped to buffer this initial insult of elevated [K] through extensive gap junctional coupling, Na+/K+ pump activity (with associated glycogen and glycolytic potential), and endfoot siphoning capability. Their abundant energy availability and alkalinizing mechanisms help sustain Na+/K+ ATPase activity under ischemic conditions. Furthermore, passive K+ uptake mechanisms and water flux mediated through aquaporin‐4 channels in endfoot processes are important energy‐independent mechanisms. Unfortunately, as the length of ischemic episode is prolonged, these mechanisms increase to a point where they begin to have repercussions on other important cellular functions. Alkalinizing mechanisms induce an elevation of [Na+]i, increasing the energy demand of Na+/K+ ATPase and leading to eventual detrimental reversal of the Na+/glutamate− cotransporter and excitotoxic damage. Prolonged ischemia also results in cell swelling and activates volume regulatory processes that release excessive excitatory amino acids, further exacerbating excitotoxic injury. In the days following ischemic injury, reactive astrocytes demonstrate increased cell size and process thickness, leading to improved spatial buffering capacity in regions outside the lesion core where there is better neuronal survival. There is a substantial heterogeneity among reactive astrocytes, with some close to the lesion showing decreased buffering capacity. However, it appears that both Na+/K+ ATPase activity (along with energy production processes) as well as passive K+ uptake mechanisms are upregulated in gliotic tissue outside the lesion to enhance the above‐mentioned homeostatic mechanisms.