| dc.description.abstracteng | Cochlear inner hair cells (IHCs) are the genuine sensory receptors that translate sound-borne cochlear vibrations into neuronal signals via ribbon synapses with the spiral ganglion neurons (SGNs). The precise mechanisms of these ribbon synapses, the first relay of the auditory pathway, are still not fully resolved. Sound intensity coding over a wide dynamic range is thought to be fractionated through the SGNs presenting distinct firing characteristics. One hypothesis is that much of this diversity reflects the presynaptic heterogeneity observed among the active zones (AZs) of IHCs. There, a single AZ is the sole input to its associated SGN and it has been demonstrated that the AZs present very distinct properties according to their position in the IHCs. The AZs facing the spiral limbus (modiolar side) show bigger ribbons correlated with a stronger Ca2+ influx activated at more depolarized membrane potentials than those at the side facing the pillar cells (pillar side). Differences in the voltage-dependent activation of the Ca2+ channels are an attractive explanation of the diverse postsynaptic spontaneous rates, where the SGNs associated with modiolar AZs with more depolarized activation range present a low spontaneous rate, while the pillar side targeting SGNs present a higher spontaneous rate. In this thesis, I first focused on deciphering the role of the synaptic ribbon at the first auditory synapse. Together with collaborators, we characterized the morphology and physiology of the ribbonless synapses by immunofluorescence and electron microscopy as well as patch–clamp/Ca2+ imaging of IHCs and systems physiology. We demonstrated a compensatory reorganization of the presynapses into several small ribbonless AZs, indicated a regulation of presynaptic Ca2+ influx by the ribbon and revealed a corresponding threshold increase as well as an impaired vesicle replenishment in the absence of the synaptic ribbon. The second part of my thesis aimed to decrypt the mechanisms setting the position-dependent heterogeneous properties of IHC AZs, putatively contributing to the wide dynamic range of sound encoding. Performing immunostainings and patch-clamp recordings combined with fast live Ca2+ imaging, we tested two different candidate mechanisms. We firstly investigated if the transcription factor Pou4f1, expressed nearly entirely in a type I SGN subpopulation targeting the IHC modiolar face. We suggested that Pou4f1 defines a subset of low spontaneous rate, high threshold SGNs by decreasing the presynaptic voltage sensitivity leading to a depolarized shift of Ca2+ influx activation of their associated modiolar AZs. Then, we focused on the planar polarity mechanisms dictating hair bundle orientation and apical surface asymmetry, and proposed a role for the Gαi/LGN complex in regulating the position-dependent AZ properties in IHCs. | de |