Disruption of Otoferlin Alters the Mode of Exocytosis at the Mouse Inner Hair Cell Ribbon Synapse.

Sound encoding relies on Ca-mediated exocytosis at the ribbon synapse between cochlear inner hair cells (IHCs) and type I spiral ganglion neurons (SGNs). Otoferlin, a multi-C domain protein, is proposed to regulate Ca-triggered exocytosis at this synapse, but the precise mechanisms of otoferlin function remain to be elucidated. Here, performing whole-cell voltage-clamp recordings of excitatory postsynaptic currents (EPSCs) from SGNs in otoferlin mutant mice, we investigated the impact of disruption at individual synapses with single release event resolution.

Pre- and postsynaptic ionotropic glutamate receptors in the auditory system of mammals.

The ionotropic glutamate receptors (iGluRs) concertedly mediate neurotransmission to convey, process, and integrate acoustic information along the auditory pathway. In order to ensure these challenging tasks, the iGluRs are variously expressed in auditory neurons in an age- and site-dependent manner. The subunit compositions of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs) are altered with development, underlying the acceleration in kinetics of excitatory postsynaptic responses.

NMDA receptor-dependent presynaptic inhibition at the calyx of Held synapse of rat pups.

-Methyl-d-aspartate receptors (NMDARs) play diverse roles in synaptic transmission, synaptic plasticity, neuronal development and neurological diseases. In addition to their postsynaptic expression, NMDARs are also expressed in presynaptic terminals at some central synapses, and their activation modulates transmitter release. However, the regulatory mechanisms of NMDAR-dependent synaptic transmission remain largely unknown.

Uniquantal release through a dynamic fusion pore is a candidate mechanism of hair cell exocytosis.

The mechanisms underlying the large amplitudes and heterogeneity of excitatory postsynaptic currents (EPSCs) at inner hair cell (IHC) ribbon synapses are unknown. Based on electrophysiology, electron and superresolution light microscopy, and modeling, we propose that uniquantal exocytosis shaped by a dynamic fusion pore is a candidate neurotransmitter release mechanism in IHCs. Modeling indicated that the extended postsynaptic AMPA receptor clusters enable large uniquantal EPSCs.

Disruption of the presynaptic cytomatrix protein bassoon degrades ribbon anchorage, multiquantal release, and sound encoding at the hair cell afferent synapse.

Inner hair cells (IHCs) of the cochlea use ribbon synapses to transmit auditory information faithfully to spiral ganglion neurons (SGNs). In the present study, we used genetic disruption of the presynaptic scaffold protein bassoon in mice to manipulate the morphology and function of the IHC synapse. Although partial-deletion mutants lacking functional bassoon (Bsn(ΔEx4/5)) had a near-complete loss of ribbons from the synapses (up to 88% ribbonless synapses), gene-trap mutants (Bsn(gt)) showed weak residual expression of bassoon and 56% ribbonless synapses, whereas the remaining 44% had a loosely anchored ribbon.

Hearing requires otoferlin-dependent efficient replenishment of synaptic vesicles in hair cells.

Inner hair cell ribbon synapses indefatigably transmit acoustic information. The proteins mediating their fast vesicle replenishment (hundreds of vesicles per s) are unknown. We found that an aspartate to glycine substitution in the C(2)F domain of the synaptic vesicle protein otoferlin impaired hearing by reducing vesicle replenishment in the pachanga mouse model of human deafness DFNB9.

G protein-dependent presynaptic inhibition mediated by AMPA receptors at the calyx of Held.

The alpha-amino-3-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is an ionotropic receptor mediating excitatory synaptic transmission, but it can also interact with intracellular messengers. Here we report that, at the calyx of Held in the rat auditory brainstem, activation of AMPARs induced inward currents in the nerve terminal and inhibited presynaptic Ca2+ currents (I(pCa)), thereby attenuating glutamatergic synaptic transmission. The AMPAR-mediated I(pCa) inhibition was disinhibited by a strong depolarizing pulse and occluded by the nonhydrolyzable GTP analog GTPgammaS loaded into the terminal.