Regeneration of Auditory Synapses

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Previous studies showed that blast-exposed and traumatic brain injury (TBI) Veterans had normal hearing thresholds but exhibited auditory synaptopathy, including central auditory processing deficits and subclinical levels of hearing dysfunction. In the peripheral auditory system, cochlear synaptopathy is the degeneration of inner hair cell synapses in the presence of nearly normal audiometric measurements and hair cells, which has been reported in age-related and noise-induced hearing loss rodent models. Knowledge of central auditory synaptopathy, however, remains very limited. Currently, the molecular mechanism critical for central auditory synaptopathy has not been determined, which restricts the understanding of central auditory synaptopathy and the development of specific treatment methods. Therefore, there is a critical need to study central auditory synapse and synaptopathy. In this proposal, spiral ganglion neuron-cochlear nucleus (SGN-CN) synapse will be investigated, as the SGN-CN synapse is the first central auditory relay that receives signals from the inner ear. Without functional SGN-CN synapses, auditory signals cannot be efficiently transferred to the brain. The objectives of this proposal are to understand the molecular mechanism critical for SGN-CN synapse integrity and develop novel therapeutic approaches to treat SGN-CN synaptopathy. Progranulin is a secreted glycoprotein that is associated with a variety of neuronal activities, including neuronal survival, neurite outgrowth, synapse formation, neuroinflammation, and neurodegeneration. The role of Progranulin in auditory synapses has not been reported. Our preliminary data suggest the relationship between Progranulin and SGN-CN synapses. Based on previous and our preliminary data, we hypothesize that Progranulin may regulate mouse SGN-CN synapse integrity. To test this hypothesis, we will characterize SGN-CN synaptopathy in the Grn-/- mouse model and determine the extent to which Progranulin plays a role in young adult mouse SGN-CN synapse integrity (Aim 1). In Aim 2, we will determine the extent to which Progranulin rescues the structure and function of SCN- CN synaptopathy. The results of this proposal will significantly advance knowledge in the integrity and regeneration of auditory synapses, which is a largely understudied VA rehabilitation research area. If cochlear synaptopathy is found in the Grn-/- mouse in this proposal, we will further characterize the role of Grn in cochlear synaptopathy and determine whether Grn-/- mouse SGN-CN synaptopathy is primary, secondary, or mixed in our future proposals. Additionally, we will investigate the role of Grn in age-related and noise-induced auditory synaptopathy. Outcome of these studies will unravel the molecular mechanisms critical for auditory synaptopathy and open new avenues to develop specific strategies for the treatment of auditory synaptopathy.