title: Viral-mediated Ntf3 overexpression disrupts innervation and hearing in nondeafened guinea pig cochleae.
abstract: Synaptopathy in the cochlea occurs when the connection between inner hair cells and the auditory nerve is disrupted, leading to impaired hearing and nerve degeneration. Experiments using transgenic mice have shown that overexpression of NT3 by supporting cells repairs synaptopathy caused by overstimulation. To accomplish such therapy in the clinical setting, it would be necessary to activate the neurotrophin receptor on auditory neurons by other means. Here we test the outcome of NT3 overexpression using viral-mediated gene transfer into the perilymph versus the endolymph of the normal guinea pig cochlea. We inoculated two different Ntf3 viral vectors, adenovirus (Adv) or adeno-associated virus (AAV) into the perilymph, to facilitate transgene expression in the mesothelial cells and cochlear duct epithelium, respectively. We assessed outcomes by comparing Auditory brainstem response (ABR) thresholds prior to that at baseline to thresholds at 1 and 3 weeks after inoculation, and then performed histologic evaluation of hair cells, nerve endings, and synaptic ribbons. We observed hearing threshold shifts as well as disorganization of peripheral nerve endings and disruption of synaptic connections between inner hair cells and peripheral nerve endings with both vectors. The data suggest that elevation of NT3 levels in the cochlear fluids can disrupt innervation and degrade hearing.
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, Kresge Hearing Research Institute, The University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Otorhinolaryngology - Head and Neck Surgery, Dankook University Hospital, Cheonan, South Korea.
authors.forename: Min Young
authors.initials: MY
authors.lastname: Lee
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, Kresge Hearing Research Institute, The University of Michigan Medical School , Ann Arbor, Michigan, USA.
authors.forename: Takaomi
authors.initials: T
authors.lastname: Kurioka
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, Kresge Hearing Research Institute, The University of Michigan Medical School , Ann Arbor, Michigan, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Nelson
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, Kresge Hearing Research Institute, The University of Michigan Medical School , Ann Arbor, Michigan, USA.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Prieskorn
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, Kresge Hearing Research Institute, The University of Michigan Medical School , Ann Arbor, Michigan, USA.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Swiderski
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, Kresge Hearing Research Institute, The University of Michigan Medical School , Ann Arbor, Michigan, USA.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Takada
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, Kresge Hearing Research Institute, The University of Michigan Medical School , Ann Arbor, Michigan, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Beyer
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, Kresge Hearing Research Institute, The University of Michigan Medical School , Ann Arbor, Michigan, USA.
authors.forename: Yehoash
authors.initials: Y
authors.lastname: Raphael