title: Ciliary neurotrophic factor (CNTF) activation of astrocytes decreases spreading depolarization susceptibility and increases potassium clearance.
abstract: Waves of spreading depolarization (SD) have been implicated in the progressive expansion of acute brain injuries. SD can persist over several days, coincident with the time course of astrocyte activation, but little is known about how astrocyte activation may influence SD susceptibility. We examined whether activation of astrocytes modified SD threshold in hippocampal slices. Injection of a lentiviral vector encoding Ciliary neurotrophic factor (CNTF) into the hippocampus in vivo, led to sustained astrocyte activation, verified by up-regulation of glial fibrillary acidic protein (GFAP) at the mRNA and protein levels, as compared to controls injected with vector encoding LacZ. In acute brain slices from LacZ controls, localized 1M KCl microinjections invariably generated SD in CA1 hippocampus, but SD was never induced with this stimulus in CNTF tissues. No significant change in intrinsic excitability was observed in CA1 neurons, but excitatory synaptic transmission was significantly reduced in CNTF samples. mRNA levels of the predominantly astrocytic Na(+) /K(+) -ATPase pump α2 subunit were higher in CNTF samples, and the kinetics of extracellular K(+) transients during matched synaptic activation were consistent with increased K(+) uptake in CNTF tissues. Supporting a role for the Na(+) /K(+) -ATPase pump in increased SD threshold, ouabain, an inhibitor of the pump, was able to generate SD in CNTF tissues. These data support the hypothesis that activated astrocytes can limit SD onset via increased K(+) clearance and suggest that therapeutic strategies targeting these glial cells could improve the outcome following acute brain injuries associated with SD.
authors.affiliation: Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Seidel
authors.forename: Mathilde
authors.initials: M
authors.lastname: Faideau
authors.forename: Isamu
authors.initials: I
authors.lastname: Aiba
authors.forename: Ulrike
authors.initials: U
authors.lastname: Pannasch
authors.forename: Carole
authors.initials: C
authors.lastname: Escartin
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rouach
authors.forename: Gilles
authors.initials: G
authors.lastname: Bonvento
authors.forename: C William
authors.initials: CW
authors.lastname: Shuttleworth
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001930:Brain Injuries / Q000378:metabolism; D016764:Cell Polarity / Q000502:physiology; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D020934:Ciliary Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D011188:Potassium
keywords: astrocyte activation; brain slice; ciliary neurotrophic factor (CNTF); hippocampus; spreading depolarization
references.citation: J Cereb Blood Flow Metab. 2008 Nov;28(11):1835-44
references.pmid: 18612316
references.citation: Brain Res. 1988 May 24;449(1-2):395-8
references.pmid: 3395856
references.citation: Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1824-8
references.pmid: 8383329
references.citation: Cereb Cortex. 2002 May;12(5):515-25
references.pmid: 11950769
references.citation: Neurol Res. 2006 Jan;28(1):71-5
references.pmid: 16464366
references.citation: Science. 2008 Dec 5;322(5907):1551-5
references.pmid: 19056987
references.citation: Glia. 2005 Jun;50(4):427-434
references.pmid: 15846805
references.citation: J Neurobiol. 1995 Dec;28(4):433-44
references.pmid: 8592104
references.citation: J Vis Exp. 2012 Nov 26;(69):e4418
references.pmid: 23222635
references.citation: J Physiol. 1996 Mar 1;491 ( Pt 2):291-305
references.pmid: 8866855
references.citation: Brain Res. 1999 Aug 14;838(1-2):37-44
references.pmid: 10446314
references.citation: Exp Neurol. 1998 Apr;150(2):171-82
references.pmid: 9527886
references.citation: Nat Med. 2011 Apr;17(4):439-47
references.pmid: 21475241
references.citation: J Neurosci. 2001 Jun 15;21(12):4225-36
references.pmid: 11404408
references.citation: Neuroscience. 2011 Sep 29;192:295-303
references.pmid: 21600270
references.citation: Glia. 2014 Apr;62(4):608-22
references.pmid: 24482245
references.citation: J Neurosci. 1991 Feb;11(2):381-91
references.pmid: 1846906
references.citation: J Neurosci. 2003 Apr 15;23(8):3196-208
references.pmid: 12716927
references.citation: Science. 1997 Oct 17;278(5337):477-83
references.pmid: 9334309
references.citation: J Physiol. 2000 Feb 1;522 Pt 3:427-42
references.pmid: 10713967
references.citation: J Neurosci. 2008 Aug 6;28(32):8014-24
references.pmid: 18685026
references.citation: J Neurol Sci. 1995 Feb;128(2):134-42
references.pmid: 7738589
references.citation: J Neurophysiol. 1990 Feb;63(2):225-39
references.pmid: 2313342
references.citation: J Neurosci. 2007 Jul 4;27(27):7094-104
references.pmid: 17611262
references.citation: J Cereb Blood Flow Metab. 2011 Jan;31(1):17-35
references.pmid: 21045864
references.citation: Cerebrovasc Brain Metab Rev. 1996 Fall;8(3):195-208
references.pmid: 8870974
references.citation: J Neurosci. 1996 Feb 1;16(3):1219-29
references.pmid: 8558250
references.citation: J Neurosci. 2003 Feb 1;23(3):766-76
references.pmid: 12574405
references.citation: Ann Neurol. 2008 Jun;63(6):720-8
references.pmid: 18496842
references.citation: Prog Brain Res. 2001;132:339-63
references.pmid: 11545002
references.citation: Methods. 1999 Jun;18(2):185-96, 179
references.pmid: 10356350
references.citation: Science. 1989 Nov 24;246(4933):1023-5
references.pmid: 2587985
references.citation: Glia. 2012 Nov;60(11):1709-20
references.pmid: 22821441
references.citation: Cephalalgia. 2009 Oct;29(10):1115-24
references.pmid: 19735537
references.citation: J Neurol Sci. 1993 Sep;118(2):109-6
references.pmid: 8229058
references.citation: Science. 2005 Oct 7;310(5745):113-6
references.pmid: 16210541
references.citation: Neurobiol Dis. 2001 Jun;8(3):433-46
references.pmid: 11442352
references.citation: J Neurochem. 1997 Nov;69(5):2132-7
references.pmid: 9349559
references.citation: Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7425-9
references.pmid: 1651505
references.citation: Exp Neurol. 2012 Jul;236(1):141-50
references.pmid: 22542945
references.citation: Nat Neurosci. 2014 Apr;17(4):549-58
references.pmid: 24584052
references.citation: Brain. 2011 May;134(Pt 5):1529-40
references.pmid: 21478187
references.citation: J Neurophysiol. 1947 Nov;10(6):409-14
references.pmid: 20268874
references.citation: J Neurosci. 1998 Sep 15;18(18):7189-99
references.pmid: 9736642
references.citation: J Neurosci. 2003 Dec 17;23(37):11602-10
references.pmid: 14684862
references.citation: J Neurosci. 1991 Jul;11(7):2187-98
references.pmid: 1906091
references.citation: J Neurophysiol. 1997 Jul;78(1):295-307
references.pmid: 9242281
references.citation: J Cereb Blood Flow Metab. 1986 Oct;6(5):607-15
references.pmid: 3760045
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Exp Neurol. 2006 Dec;202(2):302-12
references.pmid: 16904106
references.citation: Glia. 2002 Mar 15;37(4):374-8
references.pmid: 11870876
references.citation: Stroke. 2000 Jan;31(1):214-22
references.pmid: 10625740
references.citation: PLoS One. 2010 Jan 01;5(1):e8550
references.pmid: 20062544
references.citation: Brain Res Mol Brain Res. 2003 May 26;114(1):20-30
references.pmid: 12782389
references.citation: J Neurophysiol. 2000 Jul;84(1):495-512
references.pmid: 10899222
references.citation: Annu Rev Neurosci. 2001;24:31-55
references.pmid: 11283304
references.citation: Brain. 2006 Mar;129(Pt 3):778-90
references.pmid: 16364954
references.citation: Glia. 2005 Jun;50(4):407-416
references.pmid: 15846795
references.citation: Brain Res. 2004 Jun 25;1012(1-2):177-84
references.pmid: 15158175
references.citation: J Neurosci. 2006 May 31;26(22):5978-89
references.pmid: 16738240
references.citation: Cephalalgia. 2011 Dec;31(16):1601-8
references.pmid: 22013142
references.citation: Mol Neurobiol. 2008 Dec;38(3):231-41
references.pmid: 18931960
references.citation: Physiol Rev. 2001 Jul;81(3):1065-96
references.pmid: 11427692