Cochlear Neurotrophin-3 overexpression at mid-life prevents age-related inner hair cell synaptopathy and slows age-related hearing loss. 2022

Luis R Cassinotti, and Lingchao Ji, and Beatriz C Borges, and Nathan D Cass, and Aditi S Desai, and David C Kohrman, and M Charles Liberman, and Gabriel Corfas
Kresge Hearing Research Institute and Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, USA.

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 societal and economic 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. IHC synaptopathy, is an early event in cochlear aging, preceding neuronal and hair cell loss. To determine if age-related IHC 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 IHC supporting cells starting in middle age rapidly increases the amplitude of sound-evoked neural potentials compared with age-matched controls, indicating that Ntf3 produces a positive effect on cochlear function when the pathology is minimal. Furthermore, near the end of their lifespan, Ntf3-overexpressing mice have milder ARHL, with larger sound-evoked potentials along the ascending auditory pathway and reduced IHC synaptopathy compared with age-matched controls. Our results also provide evidence that an age-related decrease in cochlear Ntf3 expression contributes to ARHL and that Ntf3 supplementation could serve as a therapeutic for this prevalent disorder. Furthermore, these findings suggest that factors that regulate synaptogenesis during development could prevent age-related synaptopathy in the brain, a process involved in several central nervous system degenerative disorders.

UI MeSH Term Description Entries
D003051 Cochlea The part of the inner ear (LABYRINTH) that is concerned with hearing. It forms the anterior part of the labyrinth, as a snail-like structure that is situated almost horizontally anterior to the VESTIBULAR LABYRINTH. Cochleas
D006199 Hair Cells, Auditory, Inner Auditory sensory cells of organ of Corti, usually placed in one row medially to the core of spongy bone (the modiolus). Inner hair cells are in fewer numbers than the OUTER AUDITORY HAIR CELLS, and their STEREOCILIA are approximately twice as thick as those of the outer hair cells. Auditory Hair Cell, Inner,Auditory Hair Cells, Inner,Cochlear Inner Hair Cell,Cochlear Inner Hair Cells,Hair Cell, Auditory, Inner,Inner Auditory Hair Cell,Inner Auditory Hair Cells,Inner Hair Cells,Cell, Inner Hair,Cells, Inner Hair,Hair Cell, Inner,Hair Cells, Inner,Inner Hair Cell
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013136 Spiral Ganglion The sensory ganglion of the COCHLEAR NERVE. The cells of the spiral ganglion send fibers peripherally to the cochlear hair cells and centrally to the COCHLEAR NUCLEI of the BRAIN STEM. Ganglion of Corti,Auditory Ganglion,Spiral Ganglia,Auditory Ganglions,Ganglia, Spiral,Ganglion, Auditory,Ganglion, Spiral,Ganglions, Auditory
D013569 Synapses Specialized junctions at which a neuron communicates with a target cell. At classical synapses, a neuron's presynaptic terminal releases a chemical transmitter stored in synaptic vesicles which diffuses across a narrow synaptic cleft and activates receptors on the postsynaptic membrane of the target cell. The target may be a dendrite, cell body, or axon of another neuron, or a specialized region of a muscle or secretory cell. Neurons may also communicate via direct electrical coupling with ELECTRICAL SYNAPSES. Several other non-synaptic chemical or electric signal transmitting processes occur via extracellular mediated interactions. Synapse
D016057 Evoked Potentials, Auditory, Brain Stem Electrical waves in the CEREBRAL CORTEX generated by BRAIN STEM structures in response to auditory click stimuli. These are found to be abnormal in many patients with CEREBELLOPONTINE ANGLE lesions, MULTIPLE SCLEROSIS, or other DEMYELINATING DISEASES. Acoustic Evoked Brain Stem Potentials,Auditory Brain Stem Evoked Responses,Brain Stem Auditory Evoked Potentials,Evoked Responses, Auditory, Brain Stem,Acoustic Evoked Brain Stem Potential,Acoustic Evoked Brainstem Potential,Acoustic Evoked Brainstem Potentials,Auditory Brain Stem Evoked Response,Auditory Brain Stem Response,Auditory Brain Stem Responses,Auditory Brainstem Evoked Response,Auditory Brainstem Evoked Responses,Auditory Brainstem Responses,Brain Stem Auditory Evoked Potential,Brainstem Auditory Evoked Potential,Brainstem Auditory Evoked Potentials,Evoked Potential, Auditory, Brainstem,Evoked Potentials, Auditory, Brainstem,Evoked Response, Auditory, Brain Stem,Evoked Response, Auditory, Brainstem,Evoked Responses, Auditory, Brainstem,Auditory Brainstem Response,Brainstem Response, Auditory,Brainstem Responses, Auditory,Response, Auditory Brainstem,Responses, Auditory Brainstem
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D034381 Hearing Loss A general term for the complete or partial loss of the ability to hear from one or both ears. Deafness, Transitory,Hearing Impairment,Hearing Loss, Transitory,Hypoacusis,Transitory Hearing Loss,Deafnesses, Transitory,Hypoacuses,Loss, Hearing,Loss, Transitory Hearing,Transitory Deafness,Transitory Deafnesses,Transitory Hearing Losses

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