Encoding sound in the cochlea: from receptor potential to afferent discharge

Rutherford, Mark A.; Gersdorff, Henrique von; Goutman, Juan D.

doi:10.1113/jp279189

Cited by 35 publications

(38 citation statements)

References 258 publications

(503 reference statements)

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“…The fish lateral-line organ and the mammalian organ of Corti are examples of peripheral sensory organs that mediate fast acoustic signals via synapses between sensory hair cells and primary afferent neurons which appear to utilize GluA2-lacking, CP-AMPARs (Sebe et al, 2017 ; Hu et al, 2020 ). The faster, larger currents of CP-AMPARs are expected to drive the postsynaptic neuron to spike threshold more precisely with respect to temporal changes in the hair cell receptor potential, which may be important for mechanisms of sensory encoding such as sound source localization in the horizontal plane mediated by phase-locking (Goutman, 2012 ; Rutherford et al, 2012 , 2021 ; Li et al, 2014 ). In fish and mammals, excessive activation of AMPARs can lead to postsynaptic terminal swelling and synaptic disintegration, suggesting that CP-AMPARs may be targeted for prevention of glutamatergic excitotoxic damage.…”

Section: Discussionmentioning

confidence: 99%

Reducing Auditory Nerve Excitability by Acute Antagonism of Ca2+-Permeable AMPA Receptors

Walia

Lee

Hartsock

et al. 2021

Front. Synaptic Neurosci.

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Hearing depends on glutamatergic synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs are tetramers, where inclusion of the GluA2 subunit reduces overall channel conductance and Ca2+ permeability. Cochlear afferent synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs) contain the AMPAR subunits GluA2, 3, and 4. However, the tetrameric complement of cochlear AMPAR subunits is not known. It was recently shown in mice that chronic intracochlear delivery of IEM-1460, an antagonist selective for GluA2-lacking AMPARs [also known as Ca2+-permeable AMPARs (CP-AMPARs)], before, during, and after acoustic overexposure prevented both the trauma to ANF synapses and the ensuing reduction of cochlear nerve activity in response to sound. Surprisingly, baseline measurements of cochlear function before exposure were unaffected by chronic intracochlear delivery of IEM-1460. This suggested that cochlear afferent synapses contain GluA2-lacking CP-AMPARs alongside GluA2-containing Ca2+-impermeable AMPA receptors (CI-AMPARs), and that the former can be antagonized for protection while the latter remain conductive. Here, we investigated hearing function in the guinea pig during acute local or systemic delivery of CP-AMPAR antagonists. Acute intracochlear delivery of IEM-1460 or systemic delivery of IEM-1460 or IEM-1925 reduced the amplitude of the ANF compound action potential (CAP) significantly, for all tone levels and frequencies, by > 50% without affecting CAP thresholds or distortion product otoacoustic emissions (DPOAE). Following systemic dosing, IEM-1460 levels in cochlear perilymph were ~ 30% of blood levels, on average, consistent with pharmacokinetic properties predicting permeation of the compounds into the brain and ear. Both compounds were metabolically stable with half-lives >5 h in vitro, and elimination half-lives in vivo of 118 min (IEM-1460) and 68 min (IEM-1925). Heart rate monitoring and off-target binding assays suggest an enhanced safety profile for IEM-1925 over IEM-1460. Compound potency on CAP reduction (IC50 ~ 73 μM IEM-1460) was consistent with a mixture of GluA2-lacking and GluA2-containing AMPARs. These data strongly imply that cochlear afferent synapses of the guinea pig contain GluA2-lacking CP-AMPARs. We propose these CP-AMPARs may be acutely antagonized with systemic dosing, to protect from glutamate excitotoxicity, while transmission at GluA2-containing AMPARs persists to mediate hearing during the protection.

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Section: Discussionmentioning

confidence: 99%

Reducing Auditory Nerve Excitability by Acute Antagonism of Ca2+-Permeable AMPA Receptors

Walia

Lee

Hartsock

et al. 2021

Front. Synaptic Neurosci.

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“…Normal auditory function depends on faithful information transfer, which requires otoferlin-dependent IHC exocytosis to be indefatigable, highly efficient, and accurately synchronized (Johnson, 1980;Griesinger et al, 2005;Roux et al, 2006;Kitcher et al, 2021). Reliable and temporally precise cochlear potentials are characterized by fast rise times, short onsets, and short peak latencies Rutherford et al, 2021). Based on the findings from the present and other studies (Table 1), the severity of the phenotype associated with TSAN due to dysfunctional neurotransmitter release appears to reflect variants that alter the C2 domains of otoferlin.…”

Section: Discussionmentioning

confidence: 99%

Familial Temperature-Sensitive Auditory Neuropathy: Distinctive Clinical Courses Caused by Variants of the OTOF Gene

Zhu

Gao³

et al. 2021

Front. Cell Dev. Biol.

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Objective: To investigate the clinical course and genetic etiology of familial temperature-sensitive auditory neuropathy (TSAN), which is a very rare subtype of auditory neuropathy (AN) that involves an elevation of hearing thresholds due to an increase in the core body temperature, and to evaluate the genotype–phenotype correlations in a family with TSAN.Methods: Six members of a non-consanguineous Chinese family, including four siblings complaining of communication difficulties when febrile, were enrolled in this study. The clinical and audiological profiles of the four siblings were fully evaluated during both febrile and afebrile episodes, and the genetic etiology of hearing loss (HL) was explored using next-generation sequencing (NGS) technology. Their parents, who had no complaints of fluctuating HL due to body temperature variation, were enrolled for the genetics portion only.Results: Audiological tests during the patients’ febrile episodes met the classical diagnostic criteria for AN, including mild HL, poor speech discrimination, preserved cochlear microphonics (CMs), and absent auditory brainstem responses (ABRs). Importantly, unlike the pattern observed in previously reported cases of TSAN, the ABRs and electrocochleography (ECochG) signals of our patients improved to normal during afebrile periods. Genetic analysis identified a compound heterozygous variant of the OTOF gene (which encodes the otoferlin protein), including one previously reported pathogenic variant, c.5098G > C (p.Glu1700Gln), and one novel variant, c.4882C > A (p.Pro1628Thr). Neither of the identified variants affected the C2 domains related to the main function of otoferlin. Both variants faithfully cosegregated with TSAN within the pedigree, suggesting that OTOF is the causative gene of the autosomal recessive trait segregation in this family.Conclusion: The presence of CMs with absent (or markedly abnormal) ABRs is a reliable criterion for diagnosing AN. The severity of the phenotype caused by dysfunctional neurotransmitter release in TSAN may reflect variants that alter the C2 domains of otoferlin. The observations from this study enrich the current understanding of the phenotype and genotype of TSAN and may lay a foundation for further research on its pathogenesis.

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“…Phase locking to sound stimuli is a feature of the AN essential for sound detection, localization, and arguably for pitch perception and speech intelligibility ( Peterson and Heil, 2020 ; Yin et al, 2019 ). How these response features remain sustained, despite the limits of presynaptic mechanisms of transmitter release to ATP-generation, synaptic fatigue, and vesicle replenishment ( MacLeod and Horiuchi, 2011 ; Rutherford et al, 2021 ; Stevens and Wesseling, 1999 ; Yamamoto and Kurokawa, 1970 ) are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Intrinsic mechanical sensitivity of mammalian auditory neurons as a contributor to sound-driven neural activity

Perez-Flores

Verschooten

Lee

et al. 2022

eLife

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Mechanosensation - by which mechanical stimuli are converted into a neuronal signal - is the basis for the sensory systems of hearing, balance, and touch. Mechanosensation is unmatched in speed and its diverse range of sensitivities, reaching its highest temporal limits with the sense of hearing; however, hair cells (HCs) and the auditory nerve (AN) serve as obligatory bottlenecks for sounds to engage the brain. Like other sensory neurons, auditory neurons use the canonical pathway for neurotransmission and millisecond-duration action potentials (APs). How the auditory system utilizes the relatively slow transmission mechanisms to achieve ultrafast speed, and high audio-frequency hearing remains an enigma. Here, we address this paradox and report that the mouse, and chinchilla, AN are mechanically sensitive, and minute mechanical displacement profoundly affects its response properties. Sound-mimicking sinusoidal mechanical and electrical current stimuli affect phase-locked responses. In a phase-dependent manner, the two stimuli can also evoke suppressive responses. We propose that mechanical sensitivity interacts with synaptic responses to shape responses in the AN, including frequency tuning and temporal phase-locking. Combining neurotransmission and mechanical sensation to control spike patterns gives the mammalian AN a secondary receptor role, an emerging theme in primary neuronal functions.

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Encoding sound in the cochlea: from receptor potential to afferent discharge

Cited by 35 publications

References 258 publications

Reducing Auditory Nerve Excitability by Acute Antagonism of Ca2+-Permeable AMPA Receptors

Reducing Auditory Nerve Excitability by Acute Antagonism of Ca2+-Permeable AMPA Receptors

Familial Temperature-Sensitive Auditory Neuropathy: Distinctive Clinical Courses Caused by Variants of the OTOF Gene

Intrinsic mechanical sensitivity of mammalian auditory neurons as a contributor to sound-driven neural activity

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