title: Chronic intermittent hypoxia induces NMDA receptor-dependent plasticity and suppresses nitric oxide signaling in the mouse hypothalamic paraventricular nucleus.
abstract: 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.
authors.affiliation: Department of Neurology and Neuroscience, Division of Neurobiology, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Christal G
authors.initials: CG
authors.lastname: Coleman
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Laibaik
authors.initials: L
authors.lastname: Park
authors.forename: Josef
authors.initials: J
authors.lastname: Anrather
authors.forename: George J
authors.initials: GJ
authors.lastname: Delagrammatikas
authors.forename: June
authors.initials: J
authors.lastname: Chan
authors.forename: Joan
authors.initials: J
authors.lastname: Zhou
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Pickel
mesh_terms: 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
chemical_list: 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
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