title: Modulation of the autonomic nervous system and behaviour by acute glial cell Gq protein-coupled receptor activation in vivo.
abstract: Glial fibrillary acidic protein (GFAP)-expressing cells (GFAP(+) glial cells) are the predominant cell type in the central and peripheral nervous systems. Our understanding of the role of GFAP(+) glial cells and their signalling systems in vivo is limited due to our inability to manipulate these cells and their receptors in a cell type-specific and non-invasive manner. To circumvent this limitation, we developed a transgenic mouse line (GFAP-hM3Dq mice) that expresses an engineered Gq protein-coupled receptor (Gq-GPCR) known as hM3Dq DREADD (designer receptor exclusively activated by designer drug) selectively in GFAP(+) glial cells. The hM3Dq receptor is activated solely by a pharmacologically inert, but bioavailable, ligand (clozapine-N-oxide; CNO), while being non-responsive to endogenous GPCR ligands. In GFAP-hM3Dq mice, CNO administration increased heart rate, blood pressure and saliva formation, as well as decreased body temperature, parameters that are controlled by the autonomic nervous system (ANS). Additionally, changes in activity-related behaviour and motor coordination were observed following CNO administration. Genetically blocking inositol 1,4,5-trisphosphate (IP3)-dependent Ca(2+) increases in astrocytes failed to interfere with CNO-mediated changes in ANS function, locomotor activity or motor coordination. Our findings reveal an unexpectedly broad role of GFAP(+) glial cells in modulating complex physiology and behaviour in vivo and suggest that these effects are not dependent on IP3-dependent increases in astrocytic Ca(2+).
authors.affiliation: K. D. McCarthy: Department of Pharmacology, University of North Carolina at Chapel Hill, Genetic Medicine Building, CB# 7365, Chapel Hill, NC 27599-7365, USA. kdmc@med.unc.edu.
authors.forename: Cendra
authors.initials: C
authors.lastname: Agulhon
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Boyt
authors.forename: Alison Xiaoqiao
authors.initials: AX
authors.lastname: Xie
authors.forename: Francois
authors.initials: F
authors.lastname: Friocourt
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Ken D
authors.initials: KD
authors.lastname: McCarthy
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000502:physiology; D001341:Autonomic Nervous System / Q000378:metabolism* / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009457:Neuroglia / Q000378:metabolism* / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D005904:Glial Fibrillary Acidic Protein; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium
references.citation: ASN Neuro. 2012 Mar 22;4(2):
references.pmid: 22313347
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1995-2000
references.pmid: 17259307
references.citation: Nat Rev Neurosci. 2010 Apr;11(4):227-38
references.pmid: 20300101
references.citation: Nat Neurosci. 2011 Jan;14(1):22-4
references.pmid: 21131952
references.citation: Behav Brain Res. 2007 Jan 10;176(1):4-20
references.pmid: 16971002
references.citation: J Neurosci. 2011 Dec 7;31(49):18155-65
references.pmid: 22159127
references.citation: Nature. 2012 Aug 9;488(7410):172-7
references.pmid: 22801496
references.citation: J Clin Invest. 2011 Apr;121(4):1424-8
references.pmid: 21364278
references.citation: Cell Mol Life Sci. 2008 Jul;65(14):2191-214
references.pmid: 18488142
references.citation: J Biol Chem. 2002 Nov 29;277(48):45741-50
references.pmid: 12324450
references.citation: Science. 2012 Mar 23;335(6075):1513-6
references.pmid: 22442487
references.citation: Adv Exp Med Biol. 2012;970:307-31
references.pmid: 22351062
references.citation: Nat Methods. 2004 Oct;1(1):31-7
references.pmid: 15782150
references.citation: Science. 2010 Mar 5;327(5970):1250-4
references.pmid: 20203048
references.citation: J Neurosci. 2008 May 7;28(19):4967-73
references.pmid: 18463250
references.citation: Neuron. 2008 Sep 25;59(6):932-46
references.pmid: 18817732
references.citation: Neuropharmacology. 2005 Jul;49(1):48-58
references.pmid: 15992580
references.citation: Nature. 2013 Jan 31;493(7434):669-73
references.pmid: 23364746
references.citation: Mol Cell Endocrinol. 2012 Apr 28;353(1-2):45-56
references.pmid: 21945602
references.citation: J Physiol Paris. 2006 Mar-May;99(2-3):103-10
references.pmid: 16455236
references.citation: Nat Neurosci. 2006 Feb;9(2):260-7
references.pmid: 16388306
references.citation: Neuron. 2009 Jul 16;63(1):27-39
references.pmid: 19607790
references.citation: Neuron. 2011 Mar 10;69(5):988-1001
references.pmid: 21382557
references.citation: Glia. 2012 Jul;60(7):1013-23
references.pmid: 22228580
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5163-8
references.pmid: 17360345
references.citation: Nat Rev Neurosci. 2006 May;7(5):335-46
references.pmid: 16760914
references.citation: J Neurosci Methods. 2008 Mar 30;169(1):84-92
references.pmid: 18187203
references.citation: Nucl Med Biol. 1994 Oct;21(7):921-5
references.pmid: 9234345
references.citation: Nat Neurosci. 2011 Sep 11;14(10):1276-84
references.pmid: 21909085
references.citation: Circ Res. 2005 Jun 24;96(12):1274-81
references.pmid: 15933266
references.citation: Nature. 2012 May 13;485(7400):646-50
references.pmid: 22660328