| dc.description.abstracteng | The inner hair cell (IHC) synapse, the first relay station of the auditory system, is able to encode sound with sub-millisecond precision and without any signs of fatigue (Matthews and Fuchs, 2010; Pangršicˇ et al., 2012; Safieddine et al., 2012). Consequently, the IHC synapse manages a high rate of neurotransmitter release per active zone (AZ), which requires a fine balance between fast exocytosis and subsequent endocytosis (Pangrsic et al., 2010; Pangrsic and Vogl, 2018). The molecular physiology of this synapse is unconventional and far from understood. Furthermore, for a given sound frequency, single-AZ driven spiral ganglion neurons (SGNs) can collectively cover the whole audible spectrum of sound pressures, ranging within six orders of magnitude. How individual AZs of an IHC, which is believed to be isopotential, can drive activity of SGNs with different firing properties is also largely unknown. The presynaptic heterogeneity is one of the candidate mechanisms (Frank et al., 2009; Meyer et al., 2009; Ohn et al., 2016). This thesis provides further insight on the endocytic machinery of the IHC synapse, and the mechanisms contributing to encoding of sound pressures over a wide dynamic range. First, we combined electron tomography, membrane capacitance (Cm) measurements, systems physiology and confocal microscopy to decipher the role of AP180 in IHC synaptic transmission. Based on our results, we propose that AP180 is involved in release site clearance, clathrin assembly for clathrin-mediated endocytosis and synaptic vesicle (SV) reformation. Secondly, we explored whether the planar polarity mechanisms establishing the hair bundle orientation at the apical part of the IHC could contribute to the spatial heterogeneity of AZs at the basal part of the IHC, and thereby contribute to diverse SGN firing properties. Using patch-clamp combined with Ca2+ imaging, Cm measurements and high and superresolution light microscopy, we analyzed PTXa-expressing IHCs, in which the Gαi signaling was blocked. We propose that Gαi signaling involved in planar polarity mechanisms contributes to setting up diverse SGN firing properties (Jean et al., 2019). Lastly, we studied the IHC synaptic transfer function to understand how the heterogeneous Ca2+ signaling translates into neurotransmitter release. By dual-color imaging of synaptic Ca2+ influx and glutamate release, we discovered a heterogeneity of the Ca2+ dependence of release among the synapses, even within an individual IHC. We propose that the IHC partitions the sound information contained in the receptor potential via heterogeneous presynaptic control of release, and thereby contributes to the diverse SGN firing properties that are thought to underlie encoding over a wide dynamic range of sound pressures. | de |