title: Deletion of Aquaporin-4 Curtails Extracellular Glutamate Elevation in Cortical Spreading Depression in Awake Mice.
abstract: Cortical spreading depression (CSD) is a phenomenon that challenges the homeostatic mechanisms on which normal brain function so critically depends. Analyzing the sequence of events in CSD holds the potential of providing new insight in the physiological processes underlying normal brain function as well as the pathophysiology of neurological conditions characterized by ionic dyshomeostasis. Here, we have studied the sequential progression of CSD in awake wild-type mice and in mice lacking aquaporin-4 (AQP4) or inositol 1,4,5-triphosphate type 2 receptor (IP3R2). By the use of a novel combination of genetically encoded sensors that a novel combination - an unprecedented temporal and spatial resolution, we show that CSD leads to brisk Ca2+ signals in astrocytes and that the duration of these Ca2+ signals is shortened in the absence of AQP4 but not in the absence of IP3R2. The decrease of the astrocytic, AQP4-dependent Ca2+ signals, coincides in time and space with a decrease in the duration of extracellular glutamate overflow but not with the initial peak of the glutamate release suggesting that in CSD, extracellular glutamate accumulation is extended through AQP4-dependent glutamate release from astrocytes. The present data point to a salient glial contribution to CSD and identify AQP4 as a new target for therapy.
authors.affiliation: Department of Neurology, Oslo University Hospital, N-0027 Oslo, Norway.|GliaLab and Letten Centre, Division of Physiology, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
authors.forename: Rune
authors.initials: R
authors.lastname: Enger
authors.affiliation: GliaLab and Letten Centre, Division of Physiology, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
authors.forename: Didrik B
authors.initials: DB
authors.lastname: Dukefoss
authors.affiliation: GliaLab and Letten Centre, Division of Physiology, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
authors.forename: Wannan
authors.initials: W
authors.lastname: Tang
authors.affiliation: GliaLab and Letten Centre, Division of Physiology, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
authors.forename: Klas H
authors.initials: KH
authors.lastname: Pettersen
authors.affiliation: GliaLab and Letten Centre, Division of Physiology, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Bjørnstad
authors.affiliation: GliaLab and Letten Centre, Division of Physiology, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
authors.forename: P Johannes
authors.initials: PJ
authors.lastname: Helm
authors.affiliation: GliaLab and Letten Centre, Division of Physiology, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
authors.forename: Vidar
authors.initials: V
authors.lastname: Jensen
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute for Medical Research, D-69120 Heidelberg, Germany.|Max Planck Research Group at the Institute for Anatomy and Cell Biology, Heidelberg University, D-69120 Heidelberg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Sprengel
authors.affiliation: Division of Physiology, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
authors.forename: Koen
authors.initials: K
authors.lastname: Vervaeke
authors.affiliation: Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
authors.forename: Ole P
authors.initials: OP
authors.lastname: Ottersen
authors.affiliation: Department of Neurology, Oslo University Hospital, N-0027 Oslo, Norway.|GliaLab and Letten Centre, Division of Physiology, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
authors.forename: Erlend A
authors.initials: EA
authors.lastname: Nagelhus
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D013181:Cortical Spreading Depression / Q000502:physiology*; D015536:Down-Regulation; D045604:Extracellular Fluid / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014851:Wakefulness / Q000502:physiology*
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D018698:Glutamic Acid
keywords: AQP4; IP3R2; astrocyte; calcium; glia; homeostasis; migraine