Auditory synaptopathy due to defects of vesicle turnover at the hair cell synapse: causes and consequences

The ribbon synapse of the inner hair cell is characterized by a very high temporal precision of vesicle release and by an extremely high sustained vesicle turnover. Using animal models, we show that different molecular mechanisms can disrupt vesicle turnover and thus lead to enhanced adaptation and delayed recovery from adaptation. The hair cell-specific protein otoferlin is required for vesicle release and replenishment of the synaptic vesicle pool. Mice with different mutations in the Otof gene show varying degrees of disruption in adaptation and recovery of action potential rates in the auditory nerve. Already in some cell types of the cochlear nucleus, the impairments can be partially compensated. However, at the level of the inferior colliculus, there remains a significant limitation in the encoding of rapid fluctuations in sound level, which is consistent with the deficits in speech understanding in patients with OTOF mutations (DFNB9). Genetic defects in the genes for the calcium binding proteins CaBP1 and CaBP2 result in a very similar phenotype, which in this case can be explained by increased inactivation of synaptic calcium channels. We postulate that pathological adaptation is also to be expected in human hearing loss DFNB93 (CaBP2) and that such a phenotype represents a common mechanism of different forms of auditory synaptopathy.