Round-window delivery of neurotrophin 3 regenerates cochlear synapses after acoustic overexposure.
In acquired sensorineural hearing loss, such as that produced by noise or aging, there can be massive loss of the synaptic connections between cochlear sensory cells and primary sensory neurons, without loss of the sensory cells themselves. Because the cell bodies and central projections of these cochlear neurons survive for months to years, there is a long therapeutic window in which to re-establish functional connections and improve hearing ability. Here we show in noise-exposed mice that local delivery of neurotrophin-3 (NT-3) to the round window niche, 24 hours after an exposure that causes an immediate loss of up to 50% loss of synapses in the cochlear basal region, can regenerate pre- and post-synaptic elements at the hair cell / cochlear nerve interface. This synaptic regeneration, as documented by confocal microscopy of immunostained cochlear sensory epithelia, was coupled with a corresponding functional recovery, as seen in the suprathreshold amplitude of auditory brainstem response Wave 1. Cochlear delivery of neurotrophins in humans is likely achievable as an office procedure via transtympanic injection, making our results highly significant in a translational context.
Department of Otology and Laryngology, Harvard Medical School, Boston MA 02115, USA.|Eaton-Peabody Laboratories, Massachusetts Eye &Ear Infirmary, Boston MA 02114, USA.|Department of Otorhinolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.
Jun
J
Suzuki
Kresge Hearing Research Institute and Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA.
Gabriel
G
Corfas
Department of Otology and Laryngology, Harvard Medical School, Boston MA 02115, USA.|Eaton-Peabody Laboratories, Massachusetts Eye &Ear Infirmary, Boston MA 02114, USA.
M Charles
MC
Liberman
D000287:Administration, Topical; D000818:Animals; D012048:Correction of Hearing Impairment / Q000379:methods*; D004195:Disease Models, Animal; D006319:Hearing Loss, Sensorineural / Q000628:therapy*; D051379:Mice; D020933:Neurotrophin 3 / Q000008:administration & dosage*; D016896:Treatment Outcome
D020933:Neurotrophin 3