title: Status epilepticus induces a particular microglial activation state characterized by enhanced purinergic signaling.
abstract: Microglia cells are the resident macrophages of the CNS, and their activation plays a critical role in inflammatory reactions associated with many brain disorders, including ischemia, Alzheimer's and Parkinson's diseases, and epilepsy. However, the changes of microglia functional properties in epilepsy have rarely been studied. Here, we used a model of status epilepticus (SE) induced by intraperitoneal kainate injections to characterize the properties of microglial cells in hippocampal slices from CX3CR1(eGFP/+) mice. SE induced within 3 h an increased expression of inflammatory mediators in the hippocampus, followed by a modification of microglia morphology, a microglia proliferation, and a significant neurodegeneration in CA1. Changes in electrophysiological intrinsic membrane properties of hippocampal microglia were detected at 24-48 h after SE with, in particular, the appearance of new voltage-activated potassium currents. Consistent with the observation of an upregulation of purinergic receptor mRNAs in the hippocampus, we also provide pharmacological evidence that microglia membrane currents mediated by the activation of P2 receptors, including P2X(7), P2Y(6), and P2Y(12), were increased 48 h after SE. As a functional consequence of this modification of purinergic signaling, motility of microglia processes toward a source of P2Y(12) receptor agonist was twice as fast in the epileptic hippocampus. This study is the first functional description of microglia activation in an in vivo model of inflammation and provides evidence for the existence of a particular microglial activation state after a status epilepticus.
authors.affiliation: Inserm U603, Université Paris Descartes, Unité Mixte de Recherche-S603, Centre National de la Recherche Scientifique UMR 8154, 75006 Paris, France.
authors.forename: Elena
authors.initials: E
authors.lastname: Avignone
authors.forename: Lauriane
authors.initials: L
authors.lastname: Ulmann
authors.forename: Françoise
authors.initials: F
authors.lastname: Levavasseur
authors.forename: François
authors.initials: F
authors.lastname: Rassendren
authors.forename: Etienne
authors.initials: E
authors.lastname: Audinat
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004569:Electroencephalography; D005452:Fluoresceins; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D066298:In Vitro Techniques; D007608:Kainic Acid; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000502:physiology*; D009930:Organic Chemicals; D018408:Patch-Clamp Techniques; D011687:Purines / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics; D011983:Receptors, Purinergic / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D016207:Cytokines; D005452:Fluoresceins; D009930:Organic Chemicals; D011687:Purines; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D011983:Receptors, Purinergic; D013873:Thionucleotides; C485184:enhanced green fluorescent protein; C435731:fluoro jade; D049452:Green Fluorescent Proteins; C002480:methylthio-ADP; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D007608:Kainic Acid; C030985:purine
references.citation: J Neurochem. 2006 Nov;99(3):745-58
references.pmid: 16836656
references.citation: Nature. 2003 Aug 14;424(6950):778-83
references.pmid: 12917686
references.citation: Eur J Neurosci. 2003 Jun;17(11):2267-76
references.pmid: 12814360
references.citation: Brain Res Brain Res Rev. 2005 Apr;48(2):133-43
references.pmid: 15850652
references.citation: J Neuroimmunol. 2004 Feb;147(1-2):56-61
references.pmid: 14741428
references.citation: Nat Neurosci. 2006 Jul;9(7):917-24
references.pmid: 16732273
references.citation: Eur J Neurosci. 2000 Jul;12(7):2623-33
references.pmid: 10947836
references.citation: Brain Res. 2006 Jan 27;1070(1):215-31
references.pmid: 16403473
references.citation: Prog Brain Res. 2002;135:139-48
references.pmid: 12143336
references.citation: Mol Cell Neurosci. 2006 Dec;33(4):401-11
references.pmid: 17055293
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4103-8
references.pmid: 9108112
references.citation: Glia. 2007 Apr 15;55(6):604-16
references.pmid: 17299767
references.citation: Trends Neurosci. 2000 Nov;23(11):580-7
references.pmid: 11074268
references.citation: J Neurosci. 2005 Aug 3;25(31):7139-49
references.pmid: 16079396
references.citation: Int Rev Neurobiol. 2007;82:57-71
references.pmid: 17678955
references.citation: Brain Behav Immun. 2008 Feb;22(2):234-44
references.pmid: 17905568
references.citation: Nat Neurosci. 2007 Nov;10(11):1387-94
references.pmid: 17965659
references.citation: Neuroscience. 1983 Dec;10(4):1301-15
references.pmid: 6141539
references.citation: Epilepsia. 2008;49 Suppl 2:24-32
references.pmid: 18226169
references.citation: J Neurosci. 2007 Jan 3;27(1):234-44
references.pmid: 17202491
references.citation: Neurosci Behav Physiol. 2005 Jul;35(6):623-8
references.pmid: 16342619
references.citation: Neuroscience. 1999;93(3):915-30
references.pmid: 10473257
references.citation: Eur J Neurosci. 2006 Oct;24(8):2191-202
references.pmid: 17074044
references.citation: J Neurosci. 2007 May 2;27(18):4957-68
references.pmid: 17475804
references.citation: J Neurosci. 2008 Mar 12;28(11):2892-902
references.pmid: 18337420
references.citation: Neuroscience. 1985 Feb;14(2):375-403
references.pmid: 2859548
references.citation: Eur J Neurosci. 2000 Jun;12(6):2049-58
references.pmid: 10886344
references.citation: Neuroscience. 2004;128(2):431-41
references.pmid: 15350653
references.citation: Neurobiol Dis. 2004 Jul;16(2):321-34
references.pmid: 15193289
references.citation: J Neurosci. 2006 Nov 8;26(45):11652-64
references.pmid: 17093087
references.citation: J Immunol. 1997 Aug 1;159(3):1451-8
references.pmid: 9233643
references.citation: Nature. 2005 Dec 15;438(7070):1017-21
references.pmid: 16355225
references.citation: Glia. 2006 Aug 15;54(3):234-42
references.pmid: 16817206
references.citation: Brain Res. 1980 Nov 3;200(2):481-7
references.pmid: 7417826
references.citation: Neuroscience. 2003;122(2):551-61
references.pmid: 14614919
references.citation: J Neurochem. 2007 Sep;102(5):1447-1458
references.pmid: 17697046
references.citation: Brain Res Brain Res Rev. 2005 Apr;48(2):144-56
references.pmid: 15850653
references.citation: Yonsei Med J. 2008 Feb 29;49(1):1-18
references.pmid: 18306464
references.citation: Glia. 2007 Jun;55(8):810-21
references.pmid: 17357150
references.citation: EMBO J. 2006 Nov 1;25(21):5071-82
references.pmid: 17036048
references.citation: Brain Res. 2004 Oct 22;1024(1-2):59-76
references.pmid: 15451367
references.citation: Prog Neurobiol. 2006 Apr;78(6):327-46
references.pmid: 16697102
references.citation: Brain Res. 2000 Jan 17;853(1):49-59
references.pmid: 10627307
references.citation: Nature. 2007 Apr 26;446(7139):1091-5
references.pmid: 17410128
references.citation: Glia. 2008 Feb;56(3):331-41
references.pmid: 18098126
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Epilepsia. 2005 Nov;46(11):1724-43
references.pmid: 16302852
references.citation: Nat Neurosci. 2005 Jun;8(6):752-8
references.pmid: 15895084
references.citation: J Neuropathol Exp Neurol. 2004 Jul;63(7):686-99
references.pmid: 15290894
references.citation: Pain. 2005 Apr;114(3):386-396
references.pmid: 15777864
references.citation: J Neuroimmune Pharmacol. 2006 Jun;1(2):117-26
references.pmid: 18040778
references.citation: Mol Cell Biol. 2000 Jun;20(11):4106-14
references.pmid: 10805752
references.citation: J Neurochem. 1994 Nov;63(5):1872-9
references.pmid: 7931344
references.citation: Brain Res. 2002 Oct 18;952(2):159-69
references.pmid: 12376176
references.citation: J Neurosci. 2007 Mar 7;27(10):2596-605
references.pmid: 17344397
references.citation: Brain Res. 2000 Aug 25;874(2):123-30
references.pmid: 10960596
references.citation: Science. 2005 May 27;308(5726):1314-8
references.pmid: 15831717
references.citation: Neuron. 2002 Aug 1;35(3):419-32
references.pmid: 12165466
references.citation: Nat Neurosci. 2006 Dec;9(12):1512-9
references.pmid: 17115040
references.citation: Int Rev Neurobiol. 2007;82:247-63
references.pmid: 17678965