title: The role of spinal GABAergic circuits in the control of phrenic nerve motor output.
abstract: While supraspinal mechanisms underlying respiratory pattern formation are well characterized, the contribution of spinal circuitry to the same remains poorly understood. In this study, we tested the hypothesis that intraspinal GABAergic circuits are involved in shaping phrenic motor output. To this end, we performed bilateral phrenic nerve recordings in anesthetized adult rats and observed neurogram changes in response to knocking down expression of both isoforms (65 and 67 kDa) of glutamate decarboxylase (GAD65/67) using microinjections of anti-GAD65/67 short-interference RNA (siRNA) in the phrenic nucleus. The number of GAD65/67-positive cells was drastically reduced on the side of siRNA microinjections, especially in the lateral aspects of Rexed's laminae VII and IX in the ventral horn of cervical segment C4, but not contralateral to microinjections. We hypothesize that intraspinal GABAergic control of phrenic output is primarily phasic, but also plays an important role in tonic regulation of phrenic discharge. Also, we identified respiration-modulated GABAergic interneurons (both inspiratory and expiratory) located slightly dorsal to the phrenic nucleus. Our data provide the first direct evidence for the existence of intraspinal GABAergic circuits contributing to the formation of phrenic output. The physiological role of local intraspinal inhibition, independent of descending direct bulbospinal control, is discussed.
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania vmarchen@drexelmed.edu.
authors.forename: Vitaliy
authors.initials: V
authors.lastname: Marchenko
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Michael G Z
authors.initials: MG
authors.lastname: Ghali
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Rogers
mesh_terms: D000200:Action Potentials; D000818:Animals; D000870:Anterior Horn Cells / Q000378:metabolism*; D015536:Down-Regulation; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D007395:Interneurons / Q000378:metabolism*; D008297:Male; D008845:Microinjections; D010641:Phenotype; D010791:Phrenic Nerve / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage; D017207:Rats, Sprague-Dawley; D012119:Respiration; D012132:Respiratory Muscles / Q000294:innervation*; D009435:Synaptic Transmission; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2
keywords: GABA; interneurons; motoneurons; phrenic nerve; siRNA
references.citation: Brain Res. 1986 Jun 18;376(1):133-9
references.pmid: 3719363
references.citation: Exp Brain Res. 1989;78(3):624-32
references.pmid: 2612605
references.citation: Neuroscience. 1999;90(4):1501-13
references.pmid: 10338316
references.citation: J Physiol. 1996 Dec 15;497 ( Pt 3):803-12
references.pmid: 9003565
references.citation: Brain Res. 1985 May 6;333(2):325-9
references.pmid: 3995298
references.citation: J Appl Physiol (1985). 1987 Mar;62(3):941-5
references.pmid: 3571092
references.citation: J Neurophysiol. 2012 Oct;108(8):2134-43
references.pmid: 22815408
references.citation: Neurochem Res. 1991 Mar;16(3):215-26
references.pmid: 1780024
references.citation: Physiol Rev. 2001 Oct;81(4):1725-89
references.pmid: 11581501
references.citation: J Neurophysiol. 2009 Apr;101(4):2134-45
references.pmid: 19225173
references.citation: Brain Res. 1990 Sep 3;526(2):299-302
references.pmid: 2257486
references.citation: Prog Brain Res. 2007;165:201-20
references.pmid: 17925248
references.citation: Philos Trans R Soc Lond B Biol Sci. 2009 Sep 12;364(1529):2577-87
references.pmid: 19651658
references.citation: J Neurophysiol. 1987 Jul;58(1):105-24
references.pmid: 3039077
references.citation: Respir Physiol. 1996 Apr-May;104(1):29-37
references.pmid: 8865379
references.citation: Exp Neurol. 2013 Nov;249:20-32
references.pmid: 23954215
references.citation: J Physiol. 2007 Mar 15;579(Pt 3):765-82
references.pmid: 17204500
references.citation: Exp Brain Res. 1998 Sep;122(2):149-56
references.pmid: 9776513
references.citation: J Physiol. 1973 Oct;234(2):87P-89P
references.pmid: 4767083
references.citation: Brain Res. 1974 Dec 6;81(2):319-24
references.pmid: 4373128
references.citation: Brain Res. 1994 Jun 20;648(2):229-38
references.pmid: 7922538
references.citation: C R Acad Sci III. 1987;305(8):321-4
references.pmid: 3115504
references.citation: Respir Physiol. 1976 Feb;26(1):113-28
references.pmid: 179122
references.citation: J Neurophysiol. 1984 Apr;51(4):753-76
references.pmid: 6716123
references.citation: Trends Neurosci. 2013 Mar;36(3):152-62
references.pmid: 23254296
references.citation: Neurosci Lett. 1983 Dec 30;43(2-3):285-91
references.pmid: 6672694
references.citation: J Neurosci Res. 1995 Dec 15;42(6):742-57
references.pmid: 8847736
references.citation: J Auton Nerv Syst. 1987 Dec;21(2-3):233-9
references.pmid: 2836492
references.citation: Brain Res. 1990 Nov 12;533(1):141-6
references.pmid: 2085725
references.citation: Respir Physiol Neurobiol. 2010 Oct 31;173(3):244-55
references.pmid: 20188865
references.citation: Exp Neurol. 1987 Jun;96(3):621-34
references.pmid: 3446220
references.citation: J Physiol. 1991 Jun;437:1-25
references.pmid: 1890630
references.citation: Exp Brain Res. 1993;93(2):307-11
references.pmid: 8491269
references.citation: Respir Physiol Neurobiol. 2009 Nov 30;169(2):123-32
references.pmid: 19698805
references.citation: J Physiol. 1993 Oct;470:431-44
references.pmid: 8308735
references.citation: J Physiol. 1981;319:111-30
references.pmid: 7320908
references.citation: Neurosci Lett. 1983 Dec 23;43(1):97-101
references.pmid: 6669323
references.citation: J Neurosci. 1985 Aug;5(8):1993-2000
references.pmid: 3926961
references.citation: J Physiol. 1993 Feb;461:647-65
references.pmid: 8350278
references.citation: Brain Res. 1987 Sep 1;419(1-2):87-96
references.pmid: 3676744
references.citation: J Neurosci. 1985 Jun;5(6):1545-55
references.pmid: 4009244
references.citation: J Anat. 1988 Dec;161:171-85
references.pmid: 3254890
references.citation: Nat Rev Neurosci. 2006 Mar;7(3):232-42
references.pmid: 16495944
references.citation: J Neurochem. 1991 Feb;56(2):720-3
references.pmid: 1988566
references.citation: J Physiol. 1993 Feb;461:667-87
references.pmid: 8350279
references.citation: J Neuropathol Exp Neurol. 2011 Aug;70(8):662-77
references.pmid: 21760539
references.citation: Dis Markers. 2008;24(3):191-8
references.pmid: 18334741
references.citation: Ann N Y Acad Sci. 1963 Jun 24;109:561-70
references.pmid: 13979241
references.citation: Physiology (Bethesda). 2014 Jan;29(1):58-71
references.pmid: 24382872
references.citation: J Comp Neurol. 1981 Sep 20;201(3):441-56
references.pmid: 7276259
references.citation: J Neurophysiol. 1946 May;9:191-204
references.pmid: 21028162
references.citation: Neuroscience. 2010 Dec 1;171(2):461-84
references.pmid: 20849930
references.citation: Trends Neurosci. 2008 Oct;31(10):538-47
references.pmid: 18775573
references.citation: J Physiol. 1985 Nov;368:63-87
references.pmid: 4078753
references.citation: Neuroreport. 2000 Sep 28;11(14):3169-73
references.pmid: 11043543
references.citation: Respir Physiol Neurobiol. 2011 Oct 15;179(1):3-13
references.pmid: 21782981
references.citation: J Comp Neurol. 2008 Dec 10;511(5):692-709
references.pmid: 18924146
references.citation: J Neurosci. 1999 Mar 15;19(6):2368-80
references.pmid: 10066287
references.citation: Science. 1998 Jul 17;281(5375):419-24
references.pmid: 9665886
references.citation: J Comp Neurol. 1990 Dec 22;302(4):707-14
references.pmid: 1707065
references.citation: Pflugers Arch. 1993 Nov;425(3-4):313-20
references.pmid: 8309792
references.citation: Brain Res. 2001 Sep 28;914(1-2):34-47
references.pmid: 11578595
references.citation: J Neurophysiol. 1998 Nov;80(5):2368-77
references.pmid: 9819249
references.citation: Brain Res. 1978 Nov 24;157(2):376-80
references.pmid: 719531
references.citation: J Neurophysiol. 2006 Jul;96(1):1-2
references.pmid: 16554514
references.citation: Brain Res. 1996 Feb 26;710(1-2):150-60
references.pmid: 8963654
references.citation: J Neurophysiol. 2011 Feb;105(2):806-26
references.pmid: 21106900
references.citation: Annu Rev Physiol. 2013;75:423-52
references.pmid: 23121137
references.citation: Exp Brain Res. 1996 Nov;112(1):35-40
references.pmid: 8951404
references.citation: J Neurophysiol. 1979 Jan;42(1 Pt 1):76-90
references.pmid: 430115
references.citation: Am J Physiol. 1999 Feb;276(2 Pt 2):R420-8
references.pmid: 9950920
references.citation: Neuroscience. 2003;119(2):461-72
references.pmid: 12770560
references.citation: Respir Physiol. 1977 May;29(3):247-54
references.pmid: 882725
references.citation: J Neurosci. 1994 Mar;14(3 Pt 2):1834-55
references.pmid: 8126575
references.citation: J Neurophysiol. 2002 Nov;88(5):2215-23
references.pmid: 12424263
references.citation: Neuron. 1991 Jul;7(1):91-100
references.pmid: 2069816
references.citation: J Physiol. 1988 Jan;395:161-92
references.pmid: 3411478
references.citation: J Physiol. 1923 Mar 21;57(3-4):153-60
references.pmid: 16993609
references.citation: Neurosci Lett. 2000 Oct 20;293(1):61-4
references.pmid: 11065138
references.citation: Exp Brain Res. 1983;49(2):247-56
references.pmid: 6403368
references.citation: J Neurophysiol. 1999 Sep;82(3):1224-32
references.pmid: 10482742