title: Serotonin neurons and central respiratory chemoreception: where are we now?
abstract: Serotonin (5-hydroxytryptamine, 5-HT) neurons are widely considered to play an important role in central respiratory chemoreception. Although many studies in the past decades have supported this hypothesis, there had been concerns about its validity until recently. One recurring claim had been that 5-HT neurons are not consistently sensitive to hypercapnia in vivo. Another belief was that 5-HT neurons do not stimulate breathing; instead, they inhibit or modulate respiratory output. It was also believed by some that 5-HT neuron chemosensitivity is dependent on TASK channels, but mice with genetic deletion of TASK-1 and TASK-3 have a normal hypercapnic ventilatory response. This review explains why these principal arguments against the hypothesis are not supported by existing data. Despite repeated challenges, a large body of evidence now supports the conclusion that at least a subset of 5-HT neurons are central chemoreceptors.
authors.affiliation: St. Mary's University, One Camino Santa Maria, San Antonio, TX, USA.
authors.forename: Frida A
authors.initials: FA
authors.lastname: Teran
authors.affiliation: Interdisciplinary Graduate Program in Neuroscience, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Cory A
authors.initials: CA
authors.lastname: Massey
authors.affiliation: Interdisciplinary Graduate Program in Neuroscience, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA, USA; VAMC, Iowa City, IA, USA. Electronic address: George-Richerson@UIowa.Edu.
authors.forename: George B
authors.initials: GB
authors.lastname: Richerson
mesh_terms: D000818:Animals; D002628:Chemoreceptor Cells / Q000502:physiology*; D006801:Humans; D012125:Respiratory Center / Q000502:physiology*; D012143:Respiratory Physiological Phenomena; D059326:Serotonergic Neurons / Q000502:physiology*
keywords: 5-HT neurons; acidosis; chemoreceptors; control of breathing; hypercapnia; raphé
references.citation: J Physiol. 2004 Apr 1;556(Pt 1):235-53
references.pmid: 14724193
references.citation: Nat Neurosci. 2003 Nov;6(11):1139-40
references.pmid: 14517544
references.citation: Respir Physiol Neurobiol. 2009 May 30;167(1):9-19
references.pmid: 19118647
references.citation: Am J Respir Crit Care Med. 2003 Feb 15;167(4):563-9
references.pmid: 12406845
references.citation: J Neurosci. 2009 Aug 19;29(33):10341-9
references.pmid: 19692608
references.citation: J Appl Physiol (1985). 2001 Sep;91(3):1298-306
references.pmid: 11509529
references.citation: J Neurophysiol. 2006 Jun;95(6):3449-59
references.pmid: 16495364
references.citation: Eur J Neurosci. 1992;4(2):166-176
references.pmid: 12106379
references.citation: Cell Tissue Res. 2006 Nov;326(2):553-72
references.pmid: 16896947
references.citation: J Neurosci. 2006 Dec 6;26(49):12781-8
references.pmid: 17151281
references.citation: Can J Anaesth. 2003 Dec;50(10):1061-8
references.pmid: 14656789
references.citation: Nature. 2005 Oct 27;437(7063):1257-63
references.pmid: 16251950
references.citation: J Appl Physiol (1985). 2004 May;96(5):1909-19
references.pmid: 14752121
references.citation: Acta Physiol Scand Suppl. 1963;209:1-110
references.pmid: 14016805
references.citation: J Physiol. 2006 Apr 15;572(Pt 2):503-23
references.pmid: 16455687
references.citation: J Appl Physiol (1985). 2006 Jan;100(1):13-9
references.pmid: 16166236
references.citation: Respir Physiol. 2001 Sep;127(2-3):135-55
references.pmid: 11504586
references.citation: J Appl Physiol Respir Environ Exerc Physiol. 1983 Jan;54(1):277-83
references.pmid: 6219079
references.citation: J Physiol. 2005 Jul 15;566(Pt 2):543-57
references.pmid: 15878953
references.citation: Neuroscience. 1997 Jul;79(1):161-9
references.pmid: 9178872
references.citation: J Neurosci. 2002 Jul 15;22(14):6239-46
references.pmid: 12122082
references.citation: J Appl Physiol (1985). 2010 May;108(5):1425-32
references.pmid: 20133432
references.citation: J Neurosci. 2007 Dec 19;27(51):14049-58
references.pmid: 18094244
references.citation: J Neurosci. 2010 Jun 16;30(24):8251-62
references.pmid: 20554877
references.citation: Brain Res. 1979 Mar 9;163(1):135-50
references.pmid: 218676
references.citation: Acta Physiol Scand. 1983 Mar;117(3):427-37
references.pmid: 6410685
references.citation: J Appl Physiol (1985). 2006 Oct;101(4):1177-88
references.pmid: 16763104
references.citation: Respir Physiol Neurobiol. 2008 Dec 31;164(3):350-7
references.pmid: 18775520
references.citation: Brain Res. 1997 Jan 30;747(1):156-9
references.pmid: 9042541
references.citation: J Physiol. 2002 May 1;540(Pt 3):951-70
references.pmid: 11986382
references.citation: J Neurophysiol. 2001 May;85(5):2224-35
references.pmid: 11353037
references.citation: Brain Res. 1976 Jan 23;101(3):569-75
references.pmid: 1244990
references.citation: J Neural Transm. 1984;59(3):207-27
references.pmid: 6234377
references.citation: Science. 1985 Jul 5;229(4708):67-9
references.pmid: 3925552
references.citation: Neuroscience. 1999 Mar;90(3):1001-11
references.pmid: 10218799
references.citation: Respir Physiol Neurobiol. 2008 Dec 10;164(1-2):222-32
references.pmid: 18595785
references.citation: Neuroscience. 1990;36(1):207-16
references.pmid: 2120613
references.citation: Neuroscience. 1997 Apr;77(3):723-43
references.pmid: 9070748
references.citation: Respir Physiol. 2001 Dec;129(1-2):175-89
references.pmid: 11738653
references.citation: J Appl Physiol (1985). 2006 Oct;101(4):1097-103
references.pmid: 16794027
references.citation: Exp Physiol. 2005 May;90(3):259-66; discussion 266-9
references.pmid: 15728134
references.citation: Brain Res. 2000 Mar 31;860(1-2):119-29
references.pmid: 10727630
references.citation: J Cereb Blood Flow Metab. 1992 Mar;12(2):270-80
references.pmid: 1548299
references.citation: Brain Res. 2002 Jun 28;942(1-2):51-7
references.pmid: 12031852
references.citation: J Neurosci. 2001 Oct 1;21(19):7491-505
references.pmid: 11567039
references.citation: Br J Anaesth. 1977 Oct;49(10):957-63
references.pmid: 921874
references.citation: J Physiol. 2000 Nov 15;529 Pt 1:215-9
references.pmid: 11080263
references.citation: J Neurosci. 2009 Mar 25;29(12):3720-37
references.pmid: 19321769
references.citation: Annu Rev Neurosci. 2001;24:737-77
references.pmid: 11520917
references.citation: Neuron. 2007 Dec 6;56(5):851-65
references.pmid: 18054861
references.citation: Pflugers Arch. 2003 Feb;445(5):577-83
references.pmid: 12634929
references.citation: Neuropsychopharmacology. 1999 Aug;21(2 Suppl):24S-27S
references.pmid: 10432485
references.citation: Am J Physiol. 1999 Sep;277(3):R658-66
references.pmid: 10484481
references.citation: J Neurosci. 2000 Sep 1;20(17):6347-54
references.pmid: 10964940
references.citation: Synapse. 1990;6(4):328-37
references.pmid: 1962911
references.citation: J Neurophysiol. 2002 Dec;88(6):2899-908
references.pmid: 12466416
references.citation: J Neurosci. 2013 Oct 9;33(41):16033-44
references.pmid: 24107938
references.citation: J Clin Invest. 1979 Aug;64(2):689-93
references.pmid: 156738
references.citation: Nat Neurosci. 2004 Dec;7(12):1360-9
references.pmid: 15558061
references.citation: Exp Physiol. 1997 Jan;82(1):31-41
references.pmid: 9023504
references.citation: J Comp Neurol. 1989 Mar 1;281(1):69-96
references.pmid: 2466879
references.citation: Neurosci Lett. 1992 May 25;139(2):243-8
references.pmid: 1608554
references.citation: Am J Physiol Regul Integr Comp Physiol. 2009 Mar;296(3):R763-73
references.pmid: 19144749
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16354-9
references.pmid: 20805497
references.citation: Science. 1993 Oct 29;262(5134):679-85
references.pmid: 8235588
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4292-5
references.pmid: 15024116
references.citation: Respir Physiol. 1996 Jul;104(2-3):251-60
references.pmid: 8893371
references.citation: J Neurosci. 2011 Feb 9;31(6):1981-90
references.pmid: 21307236
references.citation: J Neurosci. 2005 Oct 5;25(40):9162-70
references.pmid: 16207875
references.citation: J Neurophysiol. 1995 Mar;73(3):933-44
references.pmid: 7608778
references.citation: J Biol Chem. 2000 Jun 2;275(22):16650-7
references.pmid: 10747866
references.citation: Am J Med. 1975 May;58(5):663-70
references.pmid: 236652
references.citation: Nat Neurosci. 1999 May;2(5):422-6
references.pmid: 10321245
references.citation: Curr Opin Neurobiol. 1997 Dec;7(6):820-5
references.pmid: 9464975
references.citation: J Neurosci. 2008 Mar 5;28(10):2495-505
references.pmid: 18322094
references.citation: Trends Mol Med. 2003 Dec;9(12):542-8
references.pmid: 14659469
references.citation: Science. 2011 Jul 29;333(6042):637-42
references.pmid: 21798952
references.citation: J Appl Physiol (1985). 2010 Apr;108(4):989-94
references.pmid: 20075260
references.citation: J Neurophysiol. 2002 Apr;87(4):2124-36
references.pmid: 11929930
references.citation: Neuroscience. 1992 Dec;51(4):941-50
references.pmid: 1336828
references.citation: Respir Physiol Neurobiol. 2009 Mar 31;166(1):4-12
references.pmid: 19056522
references.citation: J Appl Physiol (1985). 2001 Jun;90(6):2466-75
references.pmid: 11356815
references.citation: J Neurosci. 2002 Dec 15;22(24):11055-64
references.pmid: 12486201
references.citation: Respir Physiol. 2000 Jul;121(2-3):135-46
references.pmid: 10963770
references.citation: Science. 2003 Jul 11;301(5630):226-9
references.pmid: 12855812
references.citation: Brain Res. 1984 Apr 30;298(2):370-3
references.pmid: 6426700
references.citation: Nat Neurosci. 2002 May;5(5):401-2
references.pmid: 11967547
references.citation: J Physiol. 1998 Sep 1;511 ( Pt 2):433-50
references.pmid: 9706021
references.citation: J Neurosci. 2014 Jan 1;34(1):51-9
references.pmid: 24381267
references.citation: J Neurosci. 2002 Feb 15;22(4):1256-65
references.pmid: 11850453
references.citation: J Comp Neurol. 2010 Oct 1;518(19):3883-906
references.pmid: 20737591
references.citation: Br J Anaesth. 2003 Jul;91(1):40-9
references.pmid: 12821564
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14470-5
references.pmid: 12388782
references.citation: Nat Rev Neurosci. 2004 Jun;5(6):449-61
references.pmid: 15152195
references.citation: Acta Physiol Scand. 1981 Dec;113(4):541-3
references.pmid: 6182745
references.citation: Am J Physiol Cell Physiol. 2004 Sep;287(3):C682-90
references.pmid: 15115705
references.citation: Acta Physiol Scand. 1991 Mar;141(3):309-18
references.pmid: 1907074
references.citation: J Pharmacol Exp Ther. 2000 Feb;292(2):704-13
references.pmid: 10640309
references.citation: J Physiol. 2008 Apr 15;586(8):2043-8
references.pmid: 18308822
references.citation: J Neurosci. 2007 Dec 19;27(51):14128-38
references.pmid: 18094252
references.citation: NMR Biomed. 2003 Aug;16(5):261-8
references.pmid: 14648886
references.citation: Respir Physiol Neurobiol. 2009 Aug 31;168(1-2):49-58
references.pmid: 19394450
references.citation: Exp Physiol. 2005 May;90(3):247-53; discussion 253-7
references.pmid: 15728136
references.citation: Science. 2010 Jul 30;329(5991):571-5
references.pmid: 20647426
references.citation: J Neurosci. 1995 Jul;15(7 Pt 2):5346-59
references.pmid: 7623157