Chronic intermittent hypoxia induces NMDA receptor-dependent plasticity and suppresses nitric oxide signaling in the mouse hypothalamic paraventricular nucleus.
Chronic intermittent hypoxia (CIH) is a concomitant of sleep apnea that produces a slowly developing chemosensory-dependent blood pressure elevation ascribed in part to NMDA receptor-dependent plasticity and reduced nitric oxide (NO) signaling in the carotid body. The hypothalamic paraventricular nucleus (PVN) is responsive to hypoxic stress and also contains neurons that express NMDA receptors and neuronal nitric oxide synthase (nNOS). We tested the hypothesis that extended (35 d) CIH results in a decrease in the surface/synaptic availability of the essential NMDA NR1 subunit in nNOS-containing neurons and NMDA-induced NO production in the PVN of mice. As compared with controls, the 35 d CIH-exposed mice showed a significant increase in blood pressure and an increased density of NR1 immunogold particles located in the cytoplasm of nNOS-containing dendrites. Neither of these between-group differences was seen after 14 d, even though there was already a reduction in the NR1 plasmalemmal density at this time point. Patch-clamp recording of PVN neurons in slices showed a significant reduction in NMDA currents after either 14 or 35 d exposure to CIH compared with sham controls. In contrast, NO production, as measured by the NO-sensitive fluorescent dye 4-amino-5-methylamino-2',7'-difluorofluorescein, was suppressed only in the 35 d CIH group. We conclude that CIH produces a reduction in the surface/synaptic targeting of NR1 in nNOS neurons and decreases NMDA receptor-mediated currents in the PVN before the emergence of hypertension, the development of which may be enabled by suppression of NO signaling in this brain region.
Coleman
Christal G
CG
Department of Neurology and Neuroscience, Division of Neurobiology, Weill Cornell Medical College, New York, New York 10065, USA.
Wang
Gang
G
Park
Laibaik
L
Anrather
Josef
J
Delagrammatikas
George J
GJ
Chan
June
J
Zhou
Joan
J
Iadecola
Costantino
C
Pickel
Virginia M
VM
D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001784:Blood Gas Analysis / Q000379:methods; D001794:Blood Pressure / Q000502:physiology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D000860:Hypoxia / Q000473:pathology* / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission / Q000379:methods; D016202:N-Methylaspartate / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism / Q000648:ultrastructure; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism* / Q000648:ultrastructure; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014667:Vasopressins / Q000378:metabolism
D003497:Cyclic N-Oxides; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; D007093:Imidazoles; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D014667:Vasopressins; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D009569:Nitric Oxide; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D026423:S-Nitroso-N-Acetylpenicillamine; D001120:Arginine; D052248:Nitric Oxide Synthase Type I
Mol Neurobiol. 1999 Apr;19(2):151-79
10371467
J Physiol. 2008 Mar 15;586(6):1637-47
18238817
J Appl Physiol (1985). 2009 Jul;107(1):290-4
19056995
J Appl Physiol (1985). 2006 Jun;100(6):1974-82
16484362
Hypertension. 1999 Aug;34(2):309-14
10454459
Nat Med. 2006 Feb;12(2):225-9
16432513
Brain Res. 2005 Mar 10;1037(1-2):25-34
15777749
Brain Res Dev Brain Res. 1997 Jan 2;98(1):41-59
9027403
Am J Physiol Heart Circ Physiol. 2001 Sep;281(3):H995-1004
11514264
Prog Cardiovasc Dis. 2010 May-Jun;52(6):456-66
20417339
J Physiol. 2006 Dec 1;577(Pt 2):705-16
16973705
J Biol Chem. 2004 Apr 2;279(14):14307-14
14722119
Brain Res. 1997 Mar 7;750(1-2):25-40
9098526
Sleep. 2003 Feb 1;26(1):15-9
12627727
Neuroscience. 2000;101(3):637-55
11113313
Exp Neurol. 2008 Sep;213(1):57-70
18614169
Circ Res. 2003 Nov 14;93(10):990-7
14576197
J Neurosci. 2002 May 1;22(9):3608-14
11978836
Am J Physiol Heart Circ Physiol. 2001 Dec;281(6):H2328-36
11709399
Neuroscience. 2008 May 15;153(3):605-17
18424005
Neuroscience. 2003;118(3):585-601
12710969
J Appl Physiol (1985). 2003 Nov;95(5):1767-74
14555663
Brain Res Bull. 1993;32(3):207-10
8374798
Antioxid Redox Signal. 2009 Jun;11(6):1373-414
19187004
Exp Physiol. 2007 Jan;92(1):39-44
17124274
J Neurosci. 1994 Feb;14(2):667-96
8301357
J Neurosci. 2004 Sep 22;24(38):8253-64
15385609
Am J Respir Crit Care Med. 2005 Oct 1;172(7):921-9
15994465
Nat Neurosci. 2010 Mar;13(3):338-43
20118925
Mol Cell Neurosci. 1993 Apr;4(2):155-63
19912918
J Neurosci Methods. 1990 Aug;33(2-3):113-27
1977960
Synapse. 2004 Sep 15;53(4):191-201
15266550
J Neurosci. 2007 Jul 25;27(30):8101-11
17652601
Hypertension. 2002 Feb;39(2):275-80
11847197
Brain Res Bull. 1992 Apr;28(4):599-603
1617442
Clin Auton Res. 2005 Aug;15(4):254-63
16032381
ILAR J. 2009;50(3):282-8
19506314
J Physiol. 1997 Mar 15;499 ( Pt 3):733-46
9130169
J Neurosci. 2004 Aug 11;24(32):7096-109
15306643
Trends Neurosci. 2001 Apr;24(4):211-5
11250004
J Appl Physiol (1985). 2005 Nov;99(5):2028-35
16002771
Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):1073-8
18195371
J Neurophysiol. 1997 Jun;77(6):3396-400
9212285
Am J Physiol. 1994 Jan;266(1 Pt 2):R306-13
8304554
J Hypertens. 1997 Dec;15(12 Pt 2):1593-603
9488210
Cell Tissue Res. 2006 Nov;326(2):221-37
16932936
Eur J Neurosci. 2008 Jun;27(11):2783-802
18588525
Brain Res. 2002 Nov 15;955(1-2):153-60
12419531
Science. 1999 Jun 11;284(5421):1845-8
10364559
J Neurosci. 2003 Jun 15;23(12):5041-9
12832527
Neurosci Lett. 1994 Apr 25;171(1-2):13-6
8084473
Nitric Oxide. 2003 Dec;9(4):217-28
14996429
J Chem Neuroanat. 1996 Oct;11(4):243-56
8951594
J Appl Physiol (1985). 2009 Jan;106(1):259-67
18927268
Regul Pept. 2004 Jul 15;119(3):221-8
15120484
Am J Physiol. 1998 Sep;275(3):R728-34
9728069
Trends Neurosci. 1993 Dec;16(12):521-7
7509523
Cell Tissue Res. 1994 Apr;276(1):31-4
8187164
J Histochem Cytochem. 2006 Apr;54(4):427-41
16322601
Brain Res. 1992 Apr 17;577(2):261-7
1535018
J Chem Neuroanat. 2002 Nov;24(4):287-96
12406503
Prog Brain Res. 1996;107:201-22
8782521
Brain Res. 2001 Nov 23;919(2):269-82
11701139
Am J Physiol Heart Circ Physiol. 2006 Dec;291(6):H2847-56
16877560
Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2676-80
9122255
Trends Neurosci. 1997 Feb;20(2):78-84
9023876
Neuroscience. 2009 Mar 31;159(3):1079-88
19272339
J Sleep Res. 2002 Sep;11(3):265-72
12220323
Exp Physiol. 2007 May;92(3):471-9
17303648
J Pharmacol Sci. 2005 Mar;97(3):348-50
15764843
J Clin Invest. 2000 Mar;105(6):741-8
10727442
Neuroendocrinology. 1995 Aug;62(2):187-97
8584118
Respir Physiol Neurobiol. 2007 Aug 15;158(1):30-8
17442632