Synaptopathy as a Mechanism for Age-Related Vestibular Dysfunction in Mice

Age-related decline of inner ear function contributes to both hearing loss and balance disorders, which lead to impaired quality of life and falls that can result in injury and even death. The cellular mechanisms responsible for the ear's functional decline have been controversial, but hair cell loss has been considered the key cause for a long time. However, recent studies showed that in the cochlea, loss of inner hair cell (IHC) synapses precedes hair cell or neuronal loss, and this synaptopathy is an early step in the functional decline. Whether a similar process occurs in the vestibular organ, its timing and its relationship to organ dysfunction remained unknown. We compared the time course of age-related deterioration in vestibular and cochlear functions in mice as well as characterized the age-associated changes in their utricles at the histological level. We found that in the mouse, as in humans, age-related decline in vestibular evoked potentials (VsEPs) occurs later than hearing loss. As in the cochlea, deterioration of VsEPs correlates with the loss of utricular ribbon synapses but not hair cells or neuronal cell bodies. Furthermore, the age-related synaptic loss is restricted to calyceal innervations in the utricular extrastriolar region. Hence, our findings suggest that loss of extrastriolar calyceal synapses has a key role in age-related vestibular dysfunction (ARVD).