title: Aquaporin-4-dependent K(+) and water transport modeled in brain extracellular space following neuroexcitation.
abstract: Potassium (K(+)) ions released into brain extracellular space (ECS) during neuroexcitation are efficiently taken up by astrocytes. Deletion of astrocyte water channel aquaporin-4 (AQP4) in mice alters neuroexcitation by reducing ECS [K(+)] accumulation and slowing K(+) reuptake. These effects could involve AQP4-dependent: (a) K(+) permeability, (b) resting ECS volume, (c) ECS contraction during K(+) reuptake, and (d) diffusion-limited water/K(+) transport coupling. To investigate the role of these mechanisms, we compared experimental data to predictions of a model of K(+) and water uptake into astrocytes after neuronal release of K(+) into the ECS. The model computed the kinetics of ECS [K(+)] and volume, with input parameters including initial ECS volume, astrocyte K(+) conductance and water permeability, and diffusion in astrocyte cytoplasm. Numerical methods were developed to compute transport and diffusion for a nonstationary astrocyte-ECS interface. The modeling showed that mechanisms b-d, together, can predict experimentally observed impairment in K(+) reuptake from the ECS in AQP4 deficiency, as well as altered K(+) accumulation in the ECS after neuroexcitation, provided that astrocyte water permeability is sufficiently reduced in AQP4 deficiency and that solute diffusion in astrocyte cytoplasm is sufficiently low. The modeling thus provides a potential explanation for AQP4-dependent K(+)/water coupling in the ECS without requiring AQP4-dependent astrocyte K(+) permeability. Our model links the physical and ion/water transport properties of brain cells with the dynamics of neuroexcitation, and supports the conclusion that reduced AQP4-dependent water transport is responsible for defective neuroexcitation in AQP4 deficiency.
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Byung-Ju
authors.initials: BJ
authors.lastname: Jin
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Devin K
authors.initials: DK
authors.lastname: Binder
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000172:deficiency / Q000502:physiology*; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology; D002463:Cell Membrane Permeability / Q000502:physiology; D055724:Electrophysiological Phenomena / Q000502:physiology*; D005110:Extracellular Space / Q000378:metabolism*; D006801:Humans; D051379:Mice; D023421:Models, Animal; D008954:Models, Biological; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D014867:Water / Q000378:metabolism*
chemical_list: D051401:Aquaporin 4; D014867:Water; D011188:Potassium