title: Dynamics of Ionic Shifts in Cortical Spreading Depression.
abstract: Cortical spreading depression is a slowly propagating wave of near-complete depolarization of brain cells followed by temporary suppression of neuronal activity. Accumulating evidence indicates that cortical spreading depression underlies the migraine aura and that similar waves promote tissue damage in stroke, trauma, and hemorrhage. Cortical spreading depression is characterized by neuronal swelling, profound elevation of extracellular potassium and glutamate, multiphasic blood flow changes, and drop in tissue oxygen tension. The slow speed of the cortical spreading depression wave implies that it is mediated by diffusion of a chemical substance, yet the identity of this substance and the pathway it follows are unknown. Intercellular spread between gap junction-coupled neurons or glial cells and interstitial diffusion of K(+) or glutamate have been proposed. Here we use extracellular direct current potential recordings, K(+)-sensitive microelectrodes, and 2-photon imaging with ultrasensitive Ca(2+) and glutamate fluorescent probes to elucidate the spatiotemporal dynamics of ionic shifts associated with the propagation of cortical spreading depression in the visual cortex of adult living mice. Our data argue against intercellular spread of Ca(2+) carrying the cortical spreading depression wavefront and are in favor of interstitial K(+) diffusion, rather than glutamate diffusion, as the leading event in cortical spreading depression.
authors.affiliation: Department of Neurology, Oslo University Hospital, 0027 Oslo, Norway Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, 0318 Oslo, Norway Department of Molecular Medicine, Letten Centre and GliaLab, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway.
authors.forename: Rune
authors.initials: R
authors.lastname: Enger
authors.affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, 0318 Oslo, Norway Department of Molecular Medicine, Letten Centre and GliaLab, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway Department of Molecular Neurobiology, Max Planck Institute for Medical Research, D69120 Heidelberg, Germany.
authors.forename: Wannan
authors.initials: W
authors.lastname: Tang
authors.affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, 0318 Oslo, Norway Department of Molecular Medicine, Letten Centre and GliaLab, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway.
authors.forename: Gry Fluge
authors.initials: GF
authors.lastname: Vindedal
authors.affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, 0318 Oslo, Norway Department of Molecular Medicine, Letten Centre and GliaLab, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway.
authors.forename: Vidar
authors.initials: V
authors.lastname: Jensen
authors.affiliation: Department of Molecular Medicine, Letten Centre and GliaLab, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway.
authors.forename: P
authors.initials: P
authors.lastname: Johannes Helm
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute for Medical Research, D69120 Heidelberg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Sprengel
authors.affiliation: Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Loren L
authors.initials: LL
authors.lastname: Looger
authors.affiliation: Department of Neurology, Oslo University Hospital, 0027 Oslo, Norway Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, 0318 Oslo, Norway Department of Molecular Medicine, Letten Centre and GliaLab, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway Department of Molecular Neurobiology, Max Planck Institute for Medical Research, D69120 Heidelberg, Germany.
authors.forename: Erlend A
authors.initials: EA
authors.lastname: Nagelhus
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002540:Cerebral Cortex / Q000502:physiology*; D013181:Cortical Spreading Depression / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D007477:Ions / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017711:Nonlinear Dynamics; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000494:pharmacology; D016704:Synapsins / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D005904:Glial Fibrillary Acidic Protein; D007477:Ions; D008164:Luminescent Proteins; D016704:Synapsins; D018698:Glutamic Acid; D011188:Potassium
keywords: Astrocytes; calcium; glutamate; migraine; potassium
references.citation: Nat Med. 2011 Apr;17(4):439-47
references.pmid: 21475241
references.citation: J Neurosci. 2003 Oct 29;23(30):9888-96
references.pmid: 14586018
references.citation: Nat Neurosci. 2006 Feb;9(2):260-7
references.pmid: 16388306
references.citation: Proc Biol Sci. 1992 Dec 22;250(1329):287-95
references.pmid: 1362995
references.citation: Nature. 2013 Jul 18;499(7458):295-300
references.pmid: 23868258
references.citation: J Clin Invest. 2009 Jan;119(1):16-9
references.pmid: 19104145
references.citation: Neuropharmacology. 2013 Apr;67:32-6
references.pmid: 23147413
references.citation: J Neurosci. 2009 Jul 8;29(27):8621-9
references.pmid: 19587267
references.citation: J Physiol. 2012 Nov 15;590(22):5877-93
references.pmid: 22907056
references.citation: J Cereb Blood Flow Metab. 2011 Jan;31(1):68-81
references.pmid: 20859293
references.citation: Nat Rev Neurol. 2013 Nov;9(11):637-44
references.pmid: 24042483
references.citation: J Cereb Blood Flow Metab. 2011 Apr;31(4):1051-63
references.pmid: 21179069
references.citation: Brain Res. 1993 May 28;612(1-2):61-9
references.pmid: 8330214
references.citation: Nat Methods. 2013 Feb;10(2):162-70
references.pmid: 23314171
references.citation: J Neurosurg Anesthesiol. 2001 Jan;13(1):26-32
references.pmid: 11145474
references.citation: Science. 1994 Mar 25;263(5154):1768-71
references.pmid: 8134839
references.citation: Nat Rev Neurosci. 2014 Jun;15(6):379-93
references.pmid: 24857965
references.citation: J Neurophysiol. 1956 Mar;19(2):154-71
references.pmid: 13295838
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4687-92
references.pmid: 11287655
references.citation: Exp Physiol. 2005 Jan;90(1):53-9
references.pmid: 15542619
references.citation: J Neurochem. 1959 Feb;3(4):300-15
references.pmid: 13642064
references.citation: Mol Ther. 2009 Nov;17(11):1888-96
references.pmid: 19532142
references.citation: Nat Methods. 2010 Sep;7(9):755-9
references.pmid: 20693997
references.citation: Physiol Rev. 2008 Oct;88(4):1277-340
references.pmid: 18923183
references.citation: J Neurosci. 1994 Nov;14(11 Pt 2):7087-98
references.pmid: 7965100
references.citation: Brain Res. 1978 Apr 7;144(1):11-8
references.pmid: 638755
references.citation: J Neurophysiol. 1947 Nov;10(6):409-14
references.pmid: 20268874
references.citation: J Neurosci. 2011 Jun 22;31(25):9353-8
references.pmid: 21697385
references.citation: J Neurosci. 2007 Apr 11;27(15):4036-44
references.pmid: 17428981
references.citation: PLoS One. 2009;4(1):e4286
references.pmid: 19172189
references.citation: Nat Neurosci. 2007 Jun;10(6):754-62
references.pmid: 17468748
references.citation: Brain Res. 1972 Apr 14;39(1):255-9
references.pmid: 5025649
references.citation: J Neurophysiol. 1998 Mar;79(3):1587-91
references.pmid: 9497436
references.citation: Physiol Rev. 2001 Jul;81(3):1065-96
references.pmid: 11427692