title: α2δ3 is essential for normal structure and function of auditory nerve synapses and is a novel candidate for auditory processing disorders.
abstract: The auxiliary subunit α2δ3 modulates the expression and function of voltage-gated calcium channels. Here we show that α2δ3 mRNA is expressed in spiral ganglion neurons and auditory brainstem nuclei and that the protein is required for normal acoustic responses. Genetic deletion of α2δ3 led to impaired auditory processing, with reduced acoustic startle and distorted auditory brainstem responses. α2δ3(-/-) mice learned to discriminate pure tones, but they failed to discriminate temporally structured amplitude-modulated tones. Light and electron microscopy analyses revealed reduced levels of presynaptic Ca(2+) channels and smaller auditory nerve fiber terminals contacting cochlear nucleus bushy cells. Juxtacellular in vivo recordings of sound-evoked activity in α2δ3(-/-) mice demonstrated impaired transmission at these synapses. Together, our results identify a novel role for the α2δ3 auxiliary subunit in the structure and function of specific synapses in the mammalian auditory pathway and in auditory processing disorders.
authors.affiliation: University of Tübingen, Department of Otolaryngology, Tübingen Hearing Research Centre, Molecular Physiology of Hearing, 72076 Tübingen, Germany, Cluster of Excellence "Hearing4all," Institute of Audioneurotechnology and Hannover Medical School, Department of Experimental Otology, ENT Clinics, 30625 Hannover, Germany, University of Ulm, Institute of Neurobiology, 89081 Ulm, Germany, University of Tübingen, Institute of Neurobiology, 72076 Tübingen, Germany, University of Leipzig, Institute of Biology II, 04103 Leipzig, Germany, University of Hamburg, Center for Molecular Neurobiology, 20251 Hamburg, Germany, University of Kaiserslautern, Department of Biology, Neurobiology/Neurophysiology Group, 67653 Kaiserslautern, Germany, University of Kaiserslautern, Department of Biology, Animal Physiology Group, 67653 Kaiserslautern, Germany, University of Tübingen, Department of Physiology II and Tübingen Hearing Research Centre, 72076 Tübingen, Germany, and Saarland University, Department of Biophysics, 66421 Homburg/Saar, Germany.
authors.forename: Antonella
authors.initials: A
authors.lastname: Pirone
authors.forename: Simone
authors.initials: S
authors.lastname: Kurt
authors.forename: Annalisa
authors.initials: A
authors.lastname: Zuccotti
authors.forename: Lukas
authors.initials: L
authors.lastname: Rüttiger
authors.forename: Peter
authors.initials: P
authors.lastname: Pilz
authors.forename: David H
authors.initials: DH
authors.lastname: Brown
authors.forename: Christoph
authors.initials: C
authors.lastname: Franz
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.forename: Marco B
authors.initials: MB
authors.lastname: Rust
authors.forename: Rudolf
authors.initials: R
authors.lastname: Rübsamen
authors.forename: Eckhard
authors.initials: E
authors.lastname: Friauf
authors.forename: Marlies
authors.initials: M
authors.lastname: Knipper
authors.forename: Jutta
authors.initials: J
authors.lastname: Engel
mesh_terms: D000818:Animals; D001308:Auditory Perceptual Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D003056:Cochlear Nerve / Q000378:metabolism* / Q000473:pathology; D004193:Discrimination Learning / Q000502:physiology*; D004594:Electrophysiology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013136:Spiral Ganglion / Q000378:metabolism / Q000502:physiology; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: C553974:CACNA2D3 protein, mouse; D015220:Calcium Channels
keywords: CACNA2D3; Ca2+ channel; auditory discrimination learning; endbulb of Held; inner hair cell; spiral ganglion