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

Glia. 2015 Oct;63(10):1860-9. doi: 10.1002/glia.22853. Epub 2015 May 6.


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 (t1/2 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.

Keywords: AQP4; CSD; astrocyte; extracellular space; potassium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Aquaporin 4 / genetics
  • Aquaporin 4 / metabolism*
  • Brain / physiology*
  • Cell Fractionation
  • Cortical Spreading Depression / drug effects
  • Cortical Spreading Depression / genetics*
  • Electric Stimulation
  • Extracellular Space / metabolism
  • Ion-Selective Electrodes
  • Mice
  • Mice, Transgenic / genetics
  • Mice, Transgenic / metabolism*
  • Models, Theoretical
  • Potassium / pharmacology


  • Aquaporin 4
  • Potassium