gms | German Medical Science

Mammalian auditory system responds to sound pressures ranging over 6 orders of magnitude. In the cochlea, primary auditory nerve fibers — spiral ganglion neurons (SGNs) — receive input from sensory inner hair cells (IHCs). Each IHC forms synapses with up to 20 SGNs [1]. SGNs responding to the same sound frequency and potentially contacting one IHC display a large physiological diversity, whereby they differ in their spontaneous rates (SRs) of firing, sound thresholds, dynamic ranges and collectively code for the whole dynamic range of sound pressures: high-SR, low-threshold SGNs (innervating the pillar side of the IHC) respond to low sound pressures, while low-SR, high-threshold SGNs (innervating the modiolar side) are recruited at higher sound pressures. Position-dependent heterogeneity of IHC active zones (AZs) is a candidate mechanism for SGN diversity [2]: pillar AZs, which are the input for the high SR fibers display small synaptic ribbons and low Ca²⁺ influx compared to the modiolar AZs [3]. Yet the presynaptic Ca_v1.3 channels and the subsequent glutamate release at pillar AZs activate at low voltages, which is expected to drive high SRs and low thresholds in SGNs [3], [4], [5]. The mechanisms establishing the gradients of AZ properties along the pillar-modiolar axis of the IHC remain largely unknown. Single synaptic Ca²⁺ and glutamate imaging at IHC AZs combined with patch-clamp, as well as position dependent immunofluorescence analysis of AZ proteins allow for the thorough analysis of presynaptic heterogeneity in IHCs of genetically modified mice [3], [4]. We recently demonstrated that the loss of glutamatergic signaling and exocytosis in Vglut3-deficient and otoferlin-mutant mice does not disrupt IHC presynaptic heterogeneity [6]. Additionally, assessment of auditory function in-vivo by recording auditory brainstem responses (ABRs) and single SGN firing allows us to relate SGN diversity and presynaptic heterogeneity. For example, we have observed increased spontaneous firing rates and mildly reduced ABR thresholds in mice displaying hyperpolarized activation of presynaptic Ca²⁺ channels due to a point mutation in Ca_v1.3 channels, highlighting the regulation of SGN spontaneous and evoked firing by presynaptic Ca_v1.3 gating and indicating that the heterogeneous voltage dependence of Ca²⁺ channel activation at IHCs AZs contributes to the firing diversity of SGNs (Karagulyan et al., unpublished).