title: Hypoxia and hypercapnia inhibit hypothalamic orexin neurons in rats.
abstract: Evidence of impaired function of orexin neurons has been found in individuals with cardiorespiratory disorders, such as obstructive sleep apnea (OSA) and sudden infant death syndrome (SIDS), but the mechanisms responsible are unknown. Individuals with OSA and SIDS experience repetitive breathing cessations and/or rebreathing of expired air, resulting in hypoxia/hypercapnia (H/H). In this study, we examined the responses of fluorescently identified rat orexin neurons in the lateral hypothalamus to acute H/H to test if and how these neurons alter their activity and function during this challenge. Experiments were conducted in an in vitro slice preparation using voltage-clamp and current-clamp configurations. H/H (10 min) induced hyperpolarization, accompanied by rapid depression, and finally, cessation of firing activity in orexin neurons. Hypoxia alone had similar but less potent effects. H/H did not alter the frequency of inhibitory glycinergic postsynaptic currents. The frequency of GABAergic currents was diminished but only at 8-10 min of H/H. In contrast, the frequency of excitatory glutamatergic postsynaptic events was diminished as early as 2-4 min of H/H. In the presence of glutamatergic receptor blockers, the inhibitory effects of H/H on the firing activity and membrane potential of orexin neurons persisted but to a lesser extent. In conclusion, both direct alteration of postsynaptic membrane properties and diminished glutamatergic neurotransmission likely contribute to the inhibition of orexin neurons by H/H. These mechanisms could be responsible for the decreased function of orexin in individuals at risk for OSA and SIDS.
authors: Department of Pharmacology and Physiology, The George Washington University, Washington, DC; olgadl@gwu.edu.
authors: Olga
authors: O
authors: Dergacheva
authors: Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; and.
authors: Akihiro
authors: A
authors: Yamanaka
authors: Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Alan R
authors: AR
authors: Schwartz
authors: Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Vsevolod Y
authors: VY
authors: Polotsky
authors: Department of Pharmacology and Physiology, The George Washington University, Washington, DC.
authors: David
authors: D
authors: Mendelowitz
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D006935:Hypercapnia / Q000378:metabolism; D007031:Hypothalamus / Q000737:chemistry / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000378:metabolism*; D064446:Orexin Receptors / Q000032:analysis / Q000096:biosynthesis*; D000068797:Orexins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009924:Organ Culture Techniques; D010101:Oxygen Consumption / Q000502:physiology*; D051381:Rats; D055647:Rats, Transgenic
chemical_list: D064446:Orexin Receptors; D000068797:Orexins
keywords: hypercapnia; hypoxia; obstructive apnea; orexin