Abnormal Cochlear Potentials from Deaf Patients with Mutations in the Otoferlin Gene

Abstract

Otoferlin is involved in neurotransmitter release at the synapse between inner hair cells (IHCs) and auditory nerve fibres, and mutations in the OTOF gene result in severe to profound hearing loss. Abnormal sound-evoked cochlear potentials were recorded with transtympanic electrocochleography from four children with otoferlin (OTOF) mutations to evaluate physiological effects in humans of abnormal neurotransmitter release from IHCs. The subjects were profoundly deaf with absent auditory brainstem responses and preserved otoacoustic emissions consistent with auditory neuropathy. Two children were compound heterozygotes for mutations c.2732_2735dupAGCT and p.Ala964Glu; one subject was homozygous for mutation p.Phe1795Cys, and one was compound heterozygote for two novel mutations c.1609delG in exon 16 and c.1966delC in exon 18. Cochlear potentials evoked by clicks from 60 to 120 dB peak equivalent sound pressure level were compared to recordings obtained from 16 normally hearing children. Cochlear microphonic (CM) was recorded with normal amplitudes from all but one ear. After cancelling CM, cochlear potentials were of negative polarity with reduced amplitude and prolonged duration compared to controls. These cochlear potentials were recorded as low as 50-90 dB below behavioural thresholds in contrast to the close correlation in controls between cochlear potentials and behavioural threshold. Summating potential was identified in five out of eight ears with normal latency whilst auditory nerve compound action potentials were either absent or of low amplitude. Stimulation at high rates reduced amplitude and duration of the prolonged potentials, consistent with neural generation. This study suggests that mechano-electrical transduction and cochlear amplification are normal in patients with OTOF mutations. The low-amplitude prolonged negative potentials are consistent with decreased neurotransmitter release resulting in abnormal dendritic activation and impairment of auditory nerve firing.

Ouabain-Induced Cochlear Nerve Degeneration: Synaptic Loss and Plasticity in a Mouse Model of Auditory Neuropathy

“…1C). Prior reports in mutant mice lacking synaptic ribbons (Buran et al, 2010) and in humans (Santarelli et al, 2009) or mice with mutations in the gene for otoferlin, which is necessary for normal synaptic release in the IHC, both show ABR waveform abnormalities strikingly similar to those shown here, i.e., reduction or elimination of a normal wave 1 with a selective sparing of the short-latency shoulder on its rising phase. Together with the present report, these observations provide strong support for the notion that this early potential is the equivalent of the (presynaptic) "summating potential" recorded at the round window, i.e., the far-field sum of the hair cell receptor potentials (Durrant et al, 1998).…”

Auditory neuropathy — neural and synaptic mechanisms

“…For example, electrocochleography results in similar find ings for patients with OPA1-associated auditory neuro pathy and OTOF-associated auditory synapt opathy 74,127 . Moreover, in animal models of auditory synaptopathy and neuropathy, the delayed and broadened compound action potentials can arise from either presynaptic 16,17,128 or post synaptic 21 defects.…”

Audibility, speech perception and processing of temporal cues in ribbon synaptic disorders due to OTOF mutations

“…At presynaptic level, an impaired multivesicular release results in a more limited neurotransmitter availability at the synaptic cleft, with the generation of small EPSPs that have an abnormal morphology and are dispersed in time (pre-synaptic AN) (Santarelli et al, 2009;Starr et al, 2008;Wynne et al, 2013). At post-synaptic level, decreasing numbers of auditory nerve fibers and demyelination of the spared axons result in a lower auditory input to the central nervous system and a slower conduction velocity in the residual fibers (post-synaptic AN) Wynne et al, 2013).…”

“…One well-studied form of presynaptic AN is caused by mutations in the OTOF gene (Rodríguez-Ballesteros et al, 2003, 2008Santarelli et al, 2009;Starr et al, 1998;Varga et al, 2003). Otoferlin has been implicated in multivesicular release at the synapse between the IHCs and auditory nerve fibers.…”