title: Defining modulatory inputs into CNS neuronal subclasses by functional pharmacological profiling.
abstract: Previously we defined neuronal subclasses within the mouse peripheral nervous system using an experimental strategy called "constellation pharmacology." Here we demonstrate the broad applicability of constellation pharmacology by extending it to the CNS and specifically to the ventral respiratory column (VRC) of mouse brainstem, a region containing the neuronal network controlling respiratory rhythm. Analysis of dissociated cells from this locus revealed three major cell classes, each encompassing multiple subclasses. We broadly analyzed the combinations (constellations) of receptors and ion channels expressed within VRC cell classes and subclasses. These were strikingly different from the constellations of receptors and ion channels found in subclasses of peripheral neurons from mouse dorsal root ganglia. Within the VRC cell population, a subset of dissociated neurons responded to substance P, putatively corresponding to inspiratory pre-Bötzinger complex (preBötC) neurons. Using constellation pharmacology, we found that these substance P-responsive neurons also responded to histamine, and about half responded to bradykinin. Electrophysiological studies conducted in brainstem slices confirmed that preBötC neurons responsive to substance P exhibited similar responsiveness to bradykinin and histamine. The results demonstrate the predictive utility of constellation pharmacology for defining modulatory inputs into specific neuronal subclasses within central neuronal networks.
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, UT 84112.
authors.forename: Shrinivasan
authors.initials: S
authors.lastname: Raghuraman
authors.forename: Alfredo J
authors.initials: AJ
authors.lastname: Garcia
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Anderson
authors.forename: Vernon D
authors.initials: VD
authors.lastname: Twede
authors.forename: Kigen J
authors.initials: KJ
authors.lastname: Curtice
authors.forename: Kevin
authors.initials: K
authors.lastname: Chase
authors.forename: Jan-Marino
authors.initials: JM
authors.lastname: Ramirez
authors.forename: Baldomero M
authors.initials: BM
authors.lastname: Olivera
authors.forename: Russell W
authors.initials: RW
authors.lastname: Teichert
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D001933:Brain Stem / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology*; D016000:Cluster Analysis; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006632:Histamine / Q000494:pharmacology; D021621:Imaging, Three-Dimensional; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011950:Receptors, Cholinergic / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D012125:Respiratory Center / Q000166:cytology; D013373:Substance P / Q000494:pharmacology
chemical_list: D011950:Receptors, Cholinergic; D017470:Receptors, Glutamate; D013373:Substance P; D006632:Histamine; D001920:Bradykinin; D002118:Calcium
keywords: NK1 receptor; acetylcholine; calcium imaging; conotoxin; glutamate
references.citation: FASEB J. 2012 Feb;26(2):917-26
references.pmid: 22024738
references.citation: J Neurosci. 2002 May 1;22(9):3806-16
references.pmid: 11978856
references.citation: Nat Neurosci. 2008 May;11(5):538-40
references.pmid: 18391943
references.citation: J Neurosci. 2004 Aug 25;24(34):7549-56
references.pmid: 15329402
references.citation: Science. 1999 Nov 19;286(5444):1566-8
references.pmid: 10567264
references.citation: Neuron. 2013 Jan 9;77(1):19-34
references.pmid: 23312513
references.citation: Neuron. 2004 Jul 8;43(1):105-17
references.pmid: 15233921
references.citation: Cell Calcium. 2007 Sep;42(3):271-80
references.pmid: 17284334
references.citation: Nature. 1996 Oct 24;383(6602):713-6
references.pmid: 8878480
references.citation: J Physiol. 1998 Mar 15;507 ( Pt 3):895-907
references.pmid: 9508848
references.citation: Curr Opin Neurobiol. 2009 Oct;19(5):530-6
references.pmid: 19896835
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 31;109(5):1388-95
references.pmid: 22307590
references.citation: Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):2319-24
references.pmid: 24469798
references.citation: J Neurosci. 2010 Nov 3;30(44):14883-95
references.pmid: 21048147
references.citation: Glia. 2009 Jun;57(8):815-27
references.pmid: 19031447
references.citation: J Neurosci. 2003 Oct 22;23(29):9575-84
references.pmid: 14573537
references.citation: Biochemistry. 2007 Jun 5;46(22):6628-38
references.pmid: 17497892
references.citation: J Neurophysiol. 2006 Apr;95(4):2070-82
references.pmid: 16394066
references.citation: J Neurosci. 2010 Jun 16;30(24):8251-62
references.pmid: 20554877
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12758-63
references.pmid: 22778416
references.citation: Nat Neurosci. 2006 Jan;9(1):99-107
references.pmid: 16369481
references.citation: Auton Neurosci. 2013 Apr;175(1-2):26-37
references.pmid: 23497744
references.citation: Respir Physiol Neurobiol. 2010 Nov 30;174(1-2):102-10
references.pmid: 20452467
references.citation: Front Cell Neurosci. 2013 Nov 28;7:225
references.pmid: 24348328
references.citation: Mol Pain. 2012 Feb 07;8:9
references.pmid: 22314033
references.citation: Trends Neurosci. 2006 Jun;29(6):339-45
references.pmid: 16714064
references.citation: Compr Physiol. 2012 Oct;2(4):2683-731
references.pmid: 23720262
references.citation: Nat Neurosci. 2000 Jun;3(6):600-7
references.pmid: 10816317
references.citation: Eur J Neurosci. 2011 Jun;33(12):2228-37
references.pmid: 21615559
references.citation: Science. 1991 Nov 1;254(5032):726-9
references.pmid: 1683005
references.citation: J Physiol. 1996 Mar 15;491 ( Pt 3):799-812
references.pmid: 8815212
references.citation: Respir Physiol Neurobiol. 2006 Sep 28;153(2):126-38
references.pmid: 16309976