title: Aquaporin-4 regulates the velocity and frequency of cortical spreading depression in mice.
abstract: 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.
authors.affiliation: Department of Medicine and Physiology, University of California, San Francisco, California, 94143.|Department of Neurological Surgery, University of California, San Francisco, California, 94143.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yao
authors.affiliation: Department of Medicine and Physiology, University of California, San Francisco, California, 94143.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Smith
authors.affiliation: Department of Medicine and Physiology, University of California, San Francisco, California, 94143.
authors.forename: Byung-Ju
authors.initials: BJ
authors.lastname: Jin
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, California, 94143.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Zador
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, California, 94143.
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Manley
authors.affiliation: Department of Medicine and Physiology, University of California, San Francisco, California, 94143.
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000502:physiology*; D002458:Cell Fractionation; D013181:Cortical Spreading Depression / Q000187:drug effects / Q000235:genetics*; D004558:Electric Stimulation; D005110:Extracellular Space / Q000378:metabolism; D017736:Ion-Selective Electrodes; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics / Q000378:metabolism*; D008962:Models, Theoretical; D011188:Potassium / Q000494:pharmacology
chemical_list: D051401:Aquaporin 4; D011188:Potassium
keywords: AQP4; CSD; astrocyte; extracellular space; potassium