ABSTRACT
Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly. This progressive pathology often has psychological and medical comorbidities, including social isolation, depression, and cognitive decline. Despite ARHL’s enormous impact, no therapies to prevent or slow its progression exist. Loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs), a.k.a. cochlear synaptopathy, is an early event in ARHL, preceding neuronal and hair cell loss. To determine if age-related cochlear synaptopathy can be prevented, and if this impacts the time-course of ARHL, we tested the effects of cochlear overexpression of neurotrophin-3 (Ntf3) starting at middle-age. We chose Ntf3 because this neurotrophin regulates the formation of IHC-SGN synapses in the neonatal period. We now show that triggering Ntf3 overexpression by cochlear supporting cells starting in middle age rapidly increases the amplitude of sound-evoked neural potentials, indicating that Ntf3 improves cochlear function when pathology is minimal. Furthermore, near the end of their lifespan, Ntf3-overexpressing mice have milder ARHL, with enhanced cochlear neural function and reduced cochlear synaptopathy. Our results provide evidence that age-related decrease in cochlear Ntf3 expression contributes to ARHL. and Ntf3 supplementation could serve as a therapeutic for this prevalent disorder. Furthermore, these findings suggest that increased expression of factors that regulate synaptogenesis during development might prevent age-related synaptopathy, a process involved in several central nervous system degenerative disorders.
Competing Interest Statement
GC and MCL are scientific founders of Decibel Therapeutics, have equity interest in the company and have received compensation for consulting. The company was not involved in this study.
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