Abstract
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.
Highlights
Of hair cell ribbon synapses in the postnatal cochlea[17]
Considering that round-window drug delivery in humans could be accomplished via injection through the eardrum[21], our results suggest a promising therapeutic approach for the treatment of cochlear synaptopathy, and for the tinnitus and auditory processing deficits it likely causes
Prior work on noise-induced cochlear damage in mice has shown that exposure to a mid-frequency noise band for 2 hrs at intensities near 100 dB sound pressure level (SPL) can cause a permanent loss of cochlear-nerve synapses throughout the basal half of the cochlea, without causing significant permanent threshold elevations or loss of hair cells[1,22]
Summary
Of hair cell ribbon synapses in the postnatal cochlea[17]. In the early postnatal ear, NT-3 is broadly expressed in the organ of Corti, but becomes restricted to the inner hair cells (IHCs) with a longitudinal gradient (apex > base) in the adult[18,19]. Using transgenic overexpression of NT-3 by supporting cells in mice, we have shown partial synapse regeneration and partial recovery of cochlear neural responses after noise damage[17]. We show that NT-3, delivered at the round window, can regenerate hair cell synapses and restore sound-evoked neural function after a synaptopathic noise exposure. We describe techniques for surgically accessing, and delivering drugs with a thermoreversible hydrogel to the round window in mice, without jeopardizing cochlear function. Considering that round-window drug delivery in humans could be accomplished via injection through the eardrum[21], our results suggest a promising therapeutic approach for the treatment of cochlear synaptopathy, and for the tinnitus and auditory processing deficits it likely causes
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