title: Norepinephrine modulates the motility of resting and activated microglia via different adrenergic receptors.
abstract: Microglia, the resident immune cells of the central nervous system (CNS), monitor the brain for disturbances of tissue homeostasis by constantly moving their fine processes. Microglia respond to tissue damage through activation of ATP/ADP receptors followed by directional process extension to the damaged area. A common feature of several neurodegenerative diseases is the loss of norepinephrine, which might contribute to the associated neuroinflammation. We carried out a high resolution analysis of the effects of norepinephrine (NE) on microglial process dynamics in acute brain slices from mice that exhibit microglia-specific enhanced green fluorescent protein expression. Bath application of NE to the slices resulted in significant process retraction in microglia. Analysis of adrenergic receptor expression with quantitative PCR indicated that resting microglia primarily express β2 receptors but switch expression to α2A receptors under proinflammatory conditions modeled by LPS treatment. Despite the differential receptor expression, NE caused process retraction in both resting and LPS-activated microglia cultured in the gelatinous substrate Matrigel in vitro. The use of subtype-selective receptor agonists and antagonists confirmed the involvement of β2 receptors in mediating microglial process dynamics in resting cells and α2A receptors in activated cells. Co-application of NE with ATP to resting microglia blocked the ATP-induced process extension and migration in isolated microglia, and β2 receptor antagonists prolonged ATP effects in brain slice tissues, suggesting the presence of cross-talk between adrenergic and purinergic signaling in microglia. These data show that the neurotransmitter NE can modulate microglial motility, which could affect microglial functions in pathogenic situations of either elevated or reduced NE levels.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Stefka
authors.initials: S
authors.lastname: Gyoneva
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000316:Adrenergic alpha-Agonists; D018341:Receptors, Adrenergic, alpha-2; D018343:Receptors, Adrenergic, beta-2; D000255:Adenosine Triphosphate; D009638:Norepinephrine
keywords: Adrenergic Receptor; Brain Slice; Imaging; Microglia; Migration; Purinergic Receptor
references.citation: Neuroscience. 2009 Feb 6;158(3):1030-8
references.pmid: 18644426
references.citation: Nat Rev Mol Cell Biol. 2002 Sep;3(9):639-50
references.pmid: 12209124
references.citation: J Biol Chem. 2011 Feb 4;286(5):3805-14
references.pmid: 21106537
references.citation: Br J Psychiatry. 1980 Jun;136:533-41
references.pmid: 6155966
references.citation: Neurochem Int. 2009 Sep;55(4):226-34
references.pmid: 19524113
references.citation: Cell Signal. 2003 Jun;15(6):549-57
references.pmid: 12681442
references.citation: Neuropharmacology. 2004 Sep;47(3):438-49
references.pmid: 15275833
references.citation: CNS Neurol Disord Drug Targets. 2010 Apr;9(2):174-91
references.pmid: 20205642
references.citation: Nature. 1992 Mar 12;356(6365):159-61
references.pmid: 1312225
references.citation: Biochem Pharmacol. 2007 Jul 15;74(2):177-90
references.pmid: 17416354
references.citation: J Pharmacol Exp Ther. 1997 Oct;283(1):100-7
references.pmid: 9336313
references.citation: Nat Neurosci. 2007 Nov;10(11):1387-94
references.pmid: 17965659
references.citation: Ann Neurol. 1992 Nov;32(5):667-76
references.pmid: 1449247
references.citation: Neurochem Int. 2002 Nov;41(5):357-65
references.pmid: 12176079
references.citation: Nature. 1996 Oct 3;383(6599):447-50
references.pmid: 8837779
references.citation: J Physiol. 2007 Jun 15;581(Pt 3):1057-81
references.pmid: 17412766
references.citation: Brain Res. 2000 Dec 1;885(1):25-31
references.pmid: 11121526
references.citation: Biochem J. 1997 Feb 15;322 ( Pt 1):1-18
references.pmid: 9078236
references.citation: Pharmacol Ther. 1995;68(2):297-42
references.pmid: 8719972
references.citation: Brain Res Brain Res Rev. 2003 Apr;42(1):33-84
references.pmid: 12668290
references.citation: Neurobiol Aging. 2001 Jul-Aug;22(4):555-61
references.pmid: 11445255
references.citation: J Neurosci. 2001 Mar 15;21(6):1975-82
references.pmid: 11245682
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):6058-63
references.pmid: 20231476
references.citation: Glia. 2002 Nov;40(2):140-55
references.pmid: 12379902
references.citation: J Biol Chem. 1992 Aug 5;267(22):15795-801
references.pmid: 1322406
references.citation: J Comp Neurol. 1989 Sep 15;287(3):373-92
references.pmid: 2570794
references.citation: Nat Neurosci. 2009 Jul;12(7):872-8
references.pmid: 19525944
references.citation: Parkinsonism Relat Disord. 2009 Dec;15 Suppl 3:S195-9
references.pmid: 20082989
references.citation: J Biol Chem. 2005 Jan 21;280(3):1931-43
references.pmid: 15536087
references.citation: J Neurosci Res. 2002 Oct 15;70(2):232-7
references.pmid: 12271472
references.citation: Physiol Rev. 2009 Apr;89(2):535-606
references.pmid: 19342614
references.citation: Neurosci Lett. 1998 Feb 6;242(1):37-40
references.pmid: 9509999
references.citation: Nature. 1997 Nov 6;390(6655):88-91
references.pmid: 9363896
references.citation: J Neurochem. 2004 Dec;91(5):1116-24
references.pmid: 15569255
references.citation: Immunology. 1993 May;79(1):125-30
references.pmid: 8509133
references.citation: Brain Res Brain Res Rev. 2005 Apr;48(2):144-56
references.pmid: 15850653
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 21;104(34):13804-9
references.pmid: 17702867
references.citation: J Neurosci. 2010 Sep 1;30(35):11848-57
references.pmid: 20810904
references.citation: Purinergic Signal. 2007 Mar;3(1-2):117-27
references.pmid: 18404425
references.citation: Brain Res Bull. 1998;45(3):247-59
references.pmid: 9510417
references.citation: Neuropharmacology. 2002 Nov;43(6):1026-34
references.pmid: 12423672
references.citation: Mol Cell Neurosci. 2005 May;29(1):128-38
references.pmid: 15866053
references.citation: Trends Neurosci. 2007 Oct;30(10):527-35
references.pmid: 17904651
references.citation: J Neurosci. 2002 Apr 1;22(7):2434-42
references.pmid: 11923407
references.citation: J Neurosci. 2008 Sep 10;28(37):9133-44
references.pmid: 18784294
references.citation: Biochim Biophys Acta. 1993 Nov 7;1179(2):171-88
references.pmid: 7692969
references.citation: Glia. 2001 Mar 1;33(3):256-66
references.pmid: 11241743
references.citation: J Neurochem. 1991 Feb;56(2):587-95
references.pmid: 1671087
references.citation: J Neurosci Res. 2005 Aug 1;81(3):302-13
references.pmid: 15954124
references.citation: J Biol Chem. 2010 Oct 29;285(44):33816-25
references.pmid: 20739277
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: J Neurosci. 2011 Oct 5;31(40):14172-81
references.pmid: 21976502
references.citation: Nat Neurosci. 2005 Jun;8(6):752-8
references.pmid: 15895084
references.citation: Brain Res Bull. 2012 Jan 4;87(1):10-20
references.pmid: 22024597
references.citation: Brain Res. 2001 Apr 27;899(1-2):264-70
references.pmid: 11311890
references.citation: Neurosci Lett. 1989 Feb 13;97(1-2):203-8
references.pmid: 2537480
references.citation: Neurochem Int. 1996 Jul;29(1):43-53
references.pmid: 8808788
references.citation: Glia. 2012 Dec;60(12):1930-43
references.pmid: 22911652
references.citation: Mol Cell Biol. 2000 Jun;20(11):4106-14
references.pmid: 10805752
references.citation: Neurosci Lett. 1983 Aug 19;39(1):95-100
references.pmid: 6633940
references.citation: Science. 2005 May 27;308(5726):1314-8
references.pmid: 15831717
references.citation: Neuroscience. 2011 Mar 10;176:396-407
references.pmid: 21129451
references.citation: Nat Neurosci. 2006 Dec;9(12):1512-9
references.pmid: 17115040
references.citation: Glia. 2012 Sep;60(9):1366-77
references.pmid: 22638989