Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.15.097550v1?rss=1 Authors: Peineau, T., Belleudy, S., bouleau, y., Dulon, D. Abstract: Cochlear inner hair cells (IHCs) harbor a peculiar presynaptic organelle, the ribbon, which is essential for aggregating synaptic vesicles and organizing Ca2+ channels at the active zone. Emerging evidence suggests that damage to the ribbon synapses represents an important form of cochlear synaptopathy that seems prevalent in age-related sensorineural hearing loss. The functional changes occurring at these synapses during aging are not fully understood. Here, we characterized the age-related changes in IHCs of C57BL/6J mice, a strain which is known to carry a cadherin23 mutation and experiences early hearing loss with age. We found a progressive loss of synaptic ribbons with aging, starting before postnatal day 180 (P180) and reaching up to 50 % loss in middle age mice at P365. A deletion of the Otof gene, encoding the Ca2+ sensor otoferlin produced an accelerated loss of IHC ribbons with aging, with a 50 % loss by P60. In both Otof +/+ and Otof -/- C57BL/6J mice, the synaptic ribbons became larger with aging and IHCs displayed a drastic cell surface reduction with a large decrease in extrasynaptic BK-channel expression. These changes are indicative of oxidative stress and synaptic autophagy as suggested by an increased expression of the autophagosomal protein LC3B. Furthermore, whole-cell patch-clamp recordings and calcium imaging in IHCs from old Otof +/+ P365 C57BL/6J mice indicated an increase in Ca2+-channel density and a stronger exocytosis at the remaining ribbon active zones, suggesting synaptic release potentiation possibly explaining hyperacusis and recruitment in the elderly. Copy rights belong to original authors. Visit the link for more info