title: Muscarinic Acetylcholine Receptors and M-Currents Underlie Efferent-Mediated Slow Excitation in Calyx-Bearing Vestibular Afferents.
abstract: Stimulation of vestibular efferent neurons excites calyx and dimorphic (CD) afferents. This excitation consists of fast and slow components that differ >100-fold in activation kinetics and response duration. In the turtle, efferent-mediated fast excitation arises in CD afferents when the predominant efferent neurotransmitter acetylcholine (ACh) activates calyceal nicotinic ACh receptors (nAChRs); however, it is unclear whether the accompanying efferent-mediated slow excitation is also attributed to cholinergic mechanisms. To identify synaptic processes underlying efferent-mediated slow excitation, we recorded from CD afferents innervating the turtle posterior crista during electrical stimulation of efferent neurons, in combination with pharmacological probes and mechanical stimulation. Efferent-mediated slow excitation was unaffected by nAChR compounds that block efferent-mediated fast excitation, but were mimicked by muscarine and antagonized by atropine, indicating that it requires ACh and muscarinic ACh receptor (mAChR) activation. Efferent-mediated slow excitation or muscarine application enhanced the sensitivity of CD afferents to mechanical stimulation, suggesting that mAChR activation increases afferent input impedance by closing calyceal potassium channels. These observations were consistent with suppression of a muscarinic-sensitive K+-current, or M-current. Immunohistochemistry for putative M-current candidates suggested that turtle CD afferents express KCNQ3, KCNQ4, and ERG1-3 potassium channel subunits. KCNQ channels were favored as application of the selective antagonist XE991 mimicked and occluded efferent-mediated slow excitation in CD afferents. These data highlight an efferent-mediated mechanism for enhancing afferent sensitivity. They further suggest that the clinical effectiveness of mAChR antagonists in treating balance disorders may also target synaptic mechanisms in the vestibular periphery, and that KCNQ channel modulators might offer similar therapeutic value.SIGNIFICANCE STATEMENTTargeting the efferent vestibular system (EVS) pharmacologically might prove useful in ameliorating some forms of vestibular dysfunction by modifying ongoing primary vestibular input. EVS activation engages several kinetically distinct synaptic processes that profoundly alter the discharge rate and sensitivity of first-order vestibular neurons. Efferent-mediated slow excitation of vestibular afferents is of considerable interest given its ability to elevate afferent activity over an extended time course. We demonstrate for the first time that efferent-mediated slow excitation of vestibular afferents is mediated by muscarinic acetylcholine receptor (mAChR) activation and the subsequent closure of KCNQ potassium channels. The clinical effectiveness of some anti-mAChR drugs in treating motion sickness suggest that we may, in fact, already be targeting the peripheral EVS.
authors.affiliation: Departments of Otolaryngology, joseph_holt@urmc.rochester.edu.|Neuroscience, and.|Pharmacology and Physiology, University of Rochester, Rochester, New York 14642, and.
authors.forename: J Chris
authors.identifier: 0000-0001-7908-083X
authors.initials: JC
authors.lastname: Holt
authors.affiliation: Departments of Otolaryngology.
authors.forename: Paivi M
authors.identifier: 0000-0002-2498-5970
authors.initials: PM
authors.lastname: Jordan
authors.affiliation: Departments of Anatomy and Cell Biology and.|Otolaryngology, University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Anna
authors.identifier: 0000-0001-6259-0294
authors.initials: A
authors.lastname: Lysakowski
authors.affiliation: Departments of Otolaryngology.
authors.forename: Amit
authors.initials: A
authors.lastname: Shah
authors.affiliation: Departments of Otolaryngology.
authors.forename: Kathy
authors.identifier: 0000-0003-4549-9450
authors.initials: K
authors.lastname: Barsz
authors.affiliation: Departments of Otolaryngology.|Departments of Anatomy and Cell Biology and.
authors.forename: Donatella
authors.initials: D
authors.lastname: Contini
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D064032:Calbindin 2 / Q000378:metabolism; D018678:Cholinergic Agents / Q000494:pharmacology*; D004558:Electric Stimulation; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005071:Evoked Potentials / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005260:Female; D051656:KCNQ Potassium Channels / Q000378:metabolism; D008297:Male; D009434:Neural Pathways / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D009476:Neurons, Efferent / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011976:Receptors, Muscarinic / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014426:Turtles; D014722:Vestibule, Labyrinth / Q000166:cytology*
chemical_list: D064032:Calbindin 2; D018678:Cholinergic Agents; D051638:Ether-A-Go-Go Potassium Channels; D051656:KCNQ Potassium Channels; D011976:Receptors, Muscarinic
keywords: M-current; acetylcholine; calyx; muscarinic; vestibular afferent; vestibular efferent