title: Chemogenetic stimulation of the hypoglossal neurons improves upper airway patency.
abstract: Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep. OSA leads to high cardiovascular morbidity and mortality. The pathogenesis of OSA has been linked to a defect in neuromuscular control of the pharynx. There is no effective pharmacotherapy for OSA. The objective of this study was to determine whether upper airway patency can be improved using chemogenetic approach by deploying designer receptors exclusively activated by designer drug (DREADD) in the hypoglossal motorneurons. DREADD (rAAV5-hSyn-hM3(Gq)-mCherry) and control virus (rAAV5-hSyn-EGFP) were stereotactically administered to the hypoglossal nucleus of C57BL/6J mice. In 6-8 weeks genioglossus EMG and dynamic MRI of the upper airway were performed before and after administration of the DREADD ligand clozapine-N-oxide (CNO) or vehicle (saline). In DREADD-treated mice, CNO activated the genioglossus muscle and markedly dilated the pharynx, whereas saline had no effect. Control virus treated mice showed no effect of CNO. Our results suggest that chemogenetic approach can be considered as a treatment option for OSA and other motorneuron disorders.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, The John Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Otolaryngology, the University of São Paulo, São Paulo, Brazil.
authors.forename: Thomaz
authors.initials: T
authors.lastname: Fleury Curado
authors.affiliation: National Institutes of Health, National Institute of Aging, Baltimore, MD, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Fishbein
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, The John Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Huy
authors.initials: H
authors.lastname: Pho
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, The John Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Brennick
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University, Washington, DC USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Dergacheva
authors.affiliation: Department of Otolaryngology, the University of São Paulo, São Paulo, Brazil.
authors.forename: Luiz U
authors.initials: LU
authors.lastname: Sennes
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, The John Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Luu V
authors.initials: LV
authors.lastname: Pham
authors.affiliation: Department of Psychiatry, The John Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Ladenheim
authors.affiliation: National Institutes of Health, National Institute of Aging, Baltimore, MD, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Spencer
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University, Washington, DC USA.
authors.forename: David
authors.initials: D
authors.lastname: Mendelowitz
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, The John Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Schwartz
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, The John Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Vsevolod Y
authors.initials: VY
authors.lastname: Polotsky
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004576:Electromyography; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007002:Hypoglossal Nerve / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007276:Injections, Intraventricular; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010614:Pharynx / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D020181:Sleep Apnea, Obstructive / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D013238:Stereotaxic Techniques; D000097573:Red Fluorescent Protein
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D000097573:Red Fluorescent Protein; C485184:enhanced green fluorescent protein; C079149:clozapine N-oxide