Aquaporin‐4 regulates the velocity and frequency of cortical spreading depression in mice

The astrocyte water channel aquaporin‐4 (AQP4) regulates extracellular space (ECS) K + concentration ([K + ] e ) and volume dynamics following neuronal activation. Here, we investigated how AQP4‐mediated changes in [K + ] e and ECS volume affect the velocity, frequency, and amplitude of cortical spreading depression (CSD) depolarizations produced by surface KCl application in wild‐type (AQP4 +/+ ) and AQP4‐deficient (AQP4 −/− ) mice. In contrast to initial expectations, both the velocity and the frequency of CSD were significantly reduced in AQP4 −/− mice when compared with AQP4 +/+ mice, by 22% and 32%, respectively. Measurement of [K + ] e with K + ‐selective microelectrodes demonstrated an increase to ∼35 mM during spreading depolarizations in both AQP4 +/+ and AQP4 −/− mice, but the rates of [K + ] e increase (3.5 vs. 1.5 mM/s) and reuptake ( t 1/2 33 vs. 61 s) were significantly reduced in AQP4 −/− mice. ECS volume fraction measured by tetramethylammonium iontophoresis was greatly reduced during depolarizations from 0.18 to 0.053 in AQP4 +/+ mice, and 0.23 to 0.063 in AQP4 −/− mice. Analysis of the experimental data using a mathematical model of CSD propagation suggested that the reduced velocity of CSD depolarizations in AQP4 −/− mice was primarily a consequence of the slowed increase in [K + ] e during neuronal depolarization. These results demonstrate that AQP4 effects on [K + ] e and ECS volume dynamics accelerate CSD propagation. GLIA 2015;63:1860–1869