title: Impaired auditory processing and altered structure of the endbulb of Held synapse in mice lacking the GluA3 subunit of AMPA receptors.
abstract: AMPA glutamate receptor complexes with fast kinetics conferred by subunits like GluA3 and GluA4 are essential for temporal precision of synaptic transmission. The specific role of GluA3 in auditory processing and experience related changes in the auditory brainstem remain unknown. We investigated the role of the GluA3 in auditory processing by using wild type (WT) and GluA3 knockout (GluA3-KO) mice. We recorded auditory brainstem responses (ABR) to assess auditory function and used electron microscopy to evaluate the ultrastructure of the auditory nerve synapse on bushy cells (AN-BC synapse). Since labeling for GluA3 subunit increases on auditory nerve synapses within the cochlear nucleus in response to transient sound reduction, we investigated the role of GluA3 in experience-dependent changes in auditory processing. We induced transient sound reduction by plugging one ear and evaluated ABR threshold and peak amplitude recovery for up to 60 days after ear plug removal in WT and GluA3-KO mice. We found that the deletion of GluA3 leads to impaired auditory signaling that is reflected in decreased ABR peak amplitudes, an increased latency of peak 2, early onset hearing loss and reduced numbers and sizes of postsynaptic densities (PSDs) of AN-BC synapses. Additionally, the lack of GluA3 hampers ABR threshold recovery after transient ear plugging. We conclude that GluA3 is required for normal auditory signaling, normal ultrastructure of AN-BC synapses in the cochlear nucleus and normal experience-dependent changes in auditory processing after transient sound reduction.
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA.
authors.forename: Sofía
authors.initials: S
authors.lastname: García-Hernández
authors.affiliation: Niigata University Brain Research Institute, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Abe
authors.affiliation: Niigata University Brain Research Institute, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA; Department of Neurobiology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA; Center for the Neural Basis of Cognition, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA. Electronic address: mer@pitt.edu.
authors.forename: María E
authors.initials: ME
authors.lastname: Rubio
mesh_terms: D000161:Acoustic Stimulation; D000222:Adaptation, Physiological; D000818:Animals; D001307:Auditory Perception; D001522:Behavior, Animal; D003056:Cochlear Nerve / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D017626:Cochlear Nucleus / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D016057:Evoked Potentials, Auditory, Brain Stem; D020022:Genetic Predisposition to Disease; D006309:Hearing; D006316:Hearing Loss, High-Frequency / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011930:Reaction Time; D018091:Receptors, AMPA / Q000172:deficiency* / Q000235:genetics; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D013997:Time Factors
chemical_list: D018091:Receptors, AMPA; C104723:glutamate receptor ionotropic, AMPA 3
keywords: Auditory brainstem; Auditory experience; Cochlear nucleus; Endbulb of Held synapses; Postsynaptic density; Ultrastructure