title: Spinal NMDA receptor activation constrains inactivity-induced phrenic motor facilitation in Charles River Sprague-Dawley rats.
abstract: Reduced spinal synaptic inputs to phrenic motor neurons elicit a unique form of spinal plasticity known as inactivity-induced phrenic motor facilitation (iPMF). iPMF requires tumor necrosis factor-α (TNF-α) and atypical protein kinase C (aPKC) activity within spinal segments containing the phrenic motor nucleus to stabilize early, transient increases in phrenic burst amplitude into long-lasting iPMF. Here we tested the hypothesis that spinal N-methyl-d-aspartate receptor (NMDAR) activation constrains long-lasting iPMF in some rat substrains. Phrenic motor output was recorded in anesthetized, ventilated Harlan (HSD) and Charles River (CRSD) Sprague-Dawley rats exposed to a 30-min central neural apnea. HSD rats expressed a robust, long-lasting (>60 min) increase in phrenic burst amplitude (i.e., long-lasting iPMF) when respiratory neural activity was restored. By contrast, CRSD rats expressed an attenuated, transient (∼15 min) iPMF. Spinal NMDAR inhibition with DL-2-amino-5-phosphonopentanoic acid (APV) before neural apnea or shortly (4 min) prior to the resumption of respiratory neural activity revealed long-lasting iPMF in CRSD rats that was phenotypically similar to that in HSD rats. By contrast, APV did not alter iPMF expression in HSD rats. Spinal TNF-α or aPKC inhibition impaired long-lasting iPMF enabled by NMDAR inhibition in CRSD rats, suggesting that similar mechanisms give rise to long-lasting iPMF in CRSD rats with NMDAR inhibition as those giving rise to long-lasting iPMF in HSD rats. These results suggest that NMDAR activation can impose constraints on TNF-α-induced aPKC activation after neural apnea, impairing stabilization of transient iPMF into long-lasting iPMF. These data may have important implications for understanding differential responses to reduced respiratory neural activity in a heterogeneous human population.
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: K A
authors.initials: KA
authors.lastname: Streeter
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin bakert@svm.vetmed.wisc.edu.
authors.forename: T L
authors.initials: TL
authors.lastname: Baker-Herman
mesh_terms: D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D010791:Phrenic Nerve / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D014409:Tumor Necrosis Factor-alpha; C056639:2-amino-5-phosphopentanoic acid; D011493:Protein Kinase C; D014633:Valine
keywords: control of breathing; iPMF; inactivity; phrenic; plasticity
references.citation: Nat Rev Neurosci. 2010 Oct;11(10):682-96
references.pmid: 20842175
references.citation: Cell. 2006 May 19;125(4):785-99
references.pmid: 16713568
references.citation: J Trauma. 2011 Dec;71(6):1673-9
references.pmid: 21768893
references.citation: Spinal Cord. 2007 Mar;45(3):190-205
references.pmid: 17179973
references.citation: Trends Mol Med. 2006 Oct;12(10):458-60
references.pmid: 16931159
references.citation: Respir Physiol Neurobiol. 2013 Nov 1;189(2):450-64
references.pmid: 23891679
references.citation: J Neurotrauma. 1988;5(1):33-45
references.pmid: 3057216
references.citation: Respir Physiol Neurobiol. 2011 Oct 15;179(1):57-63
references.pmid: 21763470
references.citation: Science. 2002 Mar 22;295(5563):2282-5
references.pmid: 11910117
references.citation: J Neurosci. 2001 Sep 1;21(17):6617-25
references.pmid: 11517251
references.citation: Nat Neurosci. 2002 May;5(5):405-14
references.pmid: 11953750
references.citation: Brain Res. 2009 Sep 22;1290:102-10
references.pmid: 19616519
references.citation: Injury. 2005 Jul;36 Suppl 2:B113-22
references.pmid: 15993112
references.citation: Science. 2004 Jun 25;304(5679):1979-83
references.pmid: 15218151
references.citation: Brain Res. 1992 Sep 18;591(1):44-53
references.pmid: 1446232
references.citation: PLoS One. 2013 Sep 20;8(9):e75702
references.pmid: 24073275
references.citation: Ann Neurol. 1990 Jan;27(1):96-9
references.pmid: 2301932
references.citation: BMC Neurosci. 2011 Apr 14;12:31
references.pmid: 21492450
references.citation: J Physiol. 2013 Nov 15;591(22):5585-98
references.pmid: 23878370
references.citation: Nature. 2006 Apr 20;440(7087):1054-9
references.pmid: 16547515
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6760-5
references.pmid: 19346492
references.citation: J Neurosci. 2011 May 4;31(18):6627-38
references.pmid: 21543591
references.citation: Exp Neurol. 2014 Jun;256:46-56
references.pmid: 24681155
references.citation: Epilepsy Res. 2011 Oct;96(3):207-24
references.pmid: 21723093
references.citation: J Neurosci. 2002 Jul 15;22(14):6239-46
references.pmid: 12122082
references.citation: J Appl Physiol (1985). 2013 May 15;114(10):1388-95
references.pmid: 23493368
references.citation: J Pharmacol Exp Ther. 1997 Nov;283(2):511-9
references.pmid: 9353364
references.citation: J Neurosci. 2010 Sep 29;30(39):13016-20
references.pmid: 20881119
references.citation: Int J Biochem Cell Biol. 2003 Oct;35(10):1413-35
references.pmid: 12818238
references.citation: Compr Physiol. 2012 Apr;2(2):1441-62
references.pmid: 23798306
references.citation: Brain Res. 2000 Aug 25;874(2):200-9
references.pmid: 10960605
references.citation: J Neurosci. 2005 Mar 23;25(12):3219-28
references.pmid: 15788779
references.citation: J Neurosci. 2005 Dec 14;25(50):11684-92
references.pmid: 16354927
references.citation: Exp Neurol. 1989 May;104(2):118-24
references.pmid: 2651138
references.citation: J Neurotrauma. 2000 Jan;17(1):19-30
references.pmid: 10674755
references.citation: Respir Physiol Neurobiol. 2013 Nov 1;189(2):384-94
references.pmid: 23816599
references.citation: Physiol Genomics. 2001 Jan 19;4(3):175-81
references.pmid: 11160996
references.citation: J Neurotrauma. 2003 Feb;20(2):207-19
references.pmid: 12675973
references.citation: J Neurosci. 2013 Apr 17;33(16):6791-9
references.pmid: 23595738
references.citation: J Spinal Cord Med. 2007;30(4):346-54
references.pmid: 17853656
references.citation: Neuron. 2005 Jun 2;46(5):745-60
references.pmid: 15924861
references.citation: Brain Res. 1992 May 1;579(1):67-73
references.pmid: 1623408
references.citation: Respir Physiol Neurobiol. 2011 Oct 15;179(1):48-56
references.pmid: 21745601
references.citation: Neuroendocrinology. 1999 Sep;70(3):186-95
references.pmid: 10516481
references.citation: Neuron. 2008 Jun 12;58(5):673-80
references.pmid: 18549780
references.citation: J Neurosci. 2012 Nov 14;32(46):16510-20
references.pmid: 23152633
references.citation: J Neurosci. 1999 Aug 1;19(15):6248-56
references.pmid: 10414954
references.citation: J Physiol. 2006 May 1;572(Pt 3):789-98
references.pmid: 16513670
references.citation: Exp Brain Res. 1999 Nov;129(2):167-71
references.pmid: 10591890
references.citation: Life Sci. 2009 Dec 16;85(23-26):794-9
references.pmid: 19874829
references.citation: Spinal Cord. 2011 Feb;49(2):257-65
references.pmid: 20714334
references.citation: Physiol Behav. 2006 Nov 30;89(4):598-610
references.pmid: 16935312
references.citation: J Neurotrauma. 2013 Nov 1;30(21):1805-11
references.pmid: 23879467
references.citation: Neuropharmacology. 2014 Mar;78:38-44
references.pmid: 23911745
references.citation: Respir Physiol Neurobiol. 2011 Mar 15;175(3):303-9
references.pmid: 21167322
references.citation: Neurosci Lett. 1991 Apr 29;125(2):155-8
references.pmid: 1715531
references.citation: Chest. 1986 Sep;90(3):406-10
references.pmid: 3743155
references.citation: Respir Physiol Neurobiol. 2008 Jun 30;162(1):8-17
references.pmid: 18450525
references.citation: Brain Res. 2003 May 30;973(2):205-13
references.pmid: 12738064