title: Mutation of Foxo3 causes adult onset auditory neuropathy and alters cochlear synapse architecture in mice.
abstract: Auditory neuropathy is a form of hearing loss in which cochlear inner hair cells fail to correctly encode or transmit acoustic information to the brain. Few genes have been implicated in the adult-onset form of this disease. Here we show that mice lacking the transcription factor Foxo3 have adult onset hearing loss with the hallmark characteristics of auditory neuropathy, namely, elevated auditory thresholds combined with normal outer hair cell function. Using histological techniques, we demonstrate that Foxo3-dependent hearing loss is not due to a loss of cochlear hair cells or spiral ganglion neurons, both of which normally express Foxo3. Moreover, Foxo3-knock-out (KO) inner hair cells do not display reductions in numbers of synapses. Instead, we find that there are subtle structural changes in and surrounding inner hair cells. Confocal microscopy in conjunction with 3D modeling and quantitative analysis show that synaptic localization is altered in Foxo3-KO mice and Myo7a immunoreactivity is reduced. TEM demonstrates apparent afferent degeneration. Strikingly, acoustic stimulation promotes Foxo3 nuclear localization in vivo, implying a connection between cochlear activity and synaptic function maintenance. Together, these findings support a new role for the canonical damage response factor Foxo3 in contributing to the maintenance of auditory synaptic transmission.
authors.affiliation: Department of Neurobiology and Anatomy, Department of Biology, and Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
authors.forename: Felicia
authors.initials: F
authors.lastname: Gilels
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Paquette
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Zhang
authors.forename: Irfan
authors.initials: I
authors.lastname: Rahman
authors.forename: Patricia M
authors.initials: PM
authors.lastname: White
mesh_terms: D000161:Acoustic Stimulation; D000367:Age Factors; D000429:Alcohol Oxidoreductases; D000818:Animals; D000831:Animals, Newborn; D002135:Calcium-Binding Proteins / Q000378:metabolism; D056970:Co-Repressor Proteins; D003051:Cochlea / Q000254:growth & development / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem / Q000235:genetics; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D006313:Hearing Loss, Central / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D021621:Imaging, Three-Dimensional; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009154:Mutation / Q000235:genetics*; D000081412:Myosin VIIa; D009218:Myosins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure
chemical_list: D002135:Calcium-Binding Proteins; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C000631456:Myo7a protein, mouse; D000081412:Myosin VIIa; D010750:Phosphoproteins; D018091:Receptors, AMPA; C034733:oncomodulin; D000429:Alcohol Oxidoreductases; C111341:Ctbp2 protein, mouse; D009218:Myosins; C104722:glutamate receptor ionotropic, AMPA 2