Auditory neuropathy — neural and synaptic mechanisms

Moser, Tobias; Starr, Arnold

doi:10.1038/nrneurol.2016.10

Cited by 246 publications

(212 citation statements)

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“…The constitutive disruption of Cabp2 in mice likely provides an appropriate model for at least some cases of DFNB93, such as for the newly identified CABP2 mutation, which probably causes nonsense-mediated decay of Cabp2-mRNA. Hearing loss characterized by impaired ABR despite intact cochlear amplification as found in Cabp2 LacZ/LacZ mice is termed "auditory neuropathy" or "auditory synaptopathy," depending on the site of lesion (40,59). In keeping with this hypothesis, we observed otoacoustic emissions in one of the DFNB93 subjects described in the present study.…”

Section: Discussionsupporting

confidence: 84%

“…In summary, within the ear, Cabp2 is expressed in IHCs, OHCs, and vestibular hair cells but not in cochlear spiral ganglion neurons. Based on this expression pattern and our recordings of ABRs and DPOAEs, we hypothesize that the impairment of auditory processing occurs downstream of hair cell mechanoelectrical transduction and OHC amplification, most likely at the IHC synapses, a condition also known as auditory synaptopathy (40). Cabp2 Disruption Does Not Alter the Number and Gross Molecular…”

Section: Cabp2 Is Expressed In Inner Ear Hair Cells and Is Required Fmentioning

confidence: 76%

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Ca ²⁺ -binding protein 2 inhibits Ca ²⁺ -channel inactivation in mouse inner hair cells

Picher

Gehrt

Meese

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Ca 2+ -binding protein 2 (CaBP2) inhibits the inactivation of heterologously expressed voltage-gated Ca 2+ channels of type 1.3 (Ca V 1.3) and is defective in human autosomal-recessive deafness 93 (DFNB93). Here, we report a newly identified mutation in CABP2 that causes a moderate hearing impairment likely via nonsense-mediated decay of CABP2-mRNA. To study the mechanism of hearing impairment resulting from CABP2 loss of function, we disrupted Cabp2 in mice (Cabp2 LacZ/LacZ ). CaBP2 was expressed by cochlear hair cells, preferentially in inner hair cells (IHCs), and was lacking from the postsynaptic spiral ganglion neurons (SGNs). Cabp2 LacZ/LacZ mice displayed intact cochlear amplification but impaired auditory brainstem responses. Patch-clamp recordings from Cabp2 LacZ/LacZ IHCs revealed enhanced Ca 2+ -channel inactivation. The voltage dependence of activation and the number of Ca 2+ channels appeared normal in Cabp2 LacZ/LacZ mice, as were ribbon synapse counts. Recordings from single SGNs showed reduced spontaneous and sound-evoked firing rates. We propose that CaBP2 inhibits Ca V 1.3 Ca 2+ -channel inactivation, and thus sustains the availability of Ca V 1.3 Ca 2+ channels for synaptic sound encoding. Therefore, we conclude that human deafness DFNB93 is an auditory synaptopathy.H earing relies on faithful transmission of information at ribbon synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs; recently reviewed in refs. 1, 2). Ca 2+ channels at the IHC presynaptic active zone are key signaling elements because they couple the sound-evoked IHC receptor potential to the release of glutamate. IHC Ca 2+ -channel complexes are known to contain Ca V 1.3 α1 subunit (Cav1.3α1) (3-5), betasubunit 2 (Ca V β2) (6), and alpha2-delta subunit 2 (α2δ2) (7) to activate at around −60 mV (8-10), and are partially activated already at the IHC resting potential in vivo [thought to be between −55 and −45 mV (11, 12)], thereby mediating "spontaneous" glutamate release during silence (13).Compared with Ca V 1.3 channels studied in heterologous expression systems, Ca V 1.3 channels in IHCs show little inactivation, which has been attributed to inhibition of calmodulin-mediated Ca 2+ -dependent inactivation (CDI) (14-17) by Ca 2+ -binding proteins (CaBPs) (18,19) and/or the interaction of the distal and proximal regulatory domains of the Ca V 1.3α1 C terminus (20)(21)(22). This "noninactivating" phenotype of IHC Ca V 1.3 enables reliable excitation-secretion coupling during ongoing stimulation (23-25). In fact, postsynaptic spike rate adaptation during ongoing sound stimulation is thought to reflect primarily presynaptic vesicle pool depletion, with minor contributions of Ca V 1.3 inactivation or AMPA-receptor desensitization (23-26). CaBPs are calmodulin-like proteins that use three functional out of four helix-loop-helix domains (EF-hand) for Ca 2+ binding (27). They are thought to function primarily as signaling proteins (28) and differentially modulate calmodulin effectors (29,30). In addition, CaBPs m...

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Section: Discussionsupporting

confidence: 84%

Section: Cabp2 Is Expressed In Inner Ear Hair Cells and Is Required Fmentioning

confidence: 76%

Ca ²⁺ -binding protein 2 inhibits Ca ²⁺ -channel inactivation in mouse inner hair cells

Picher

Gehrt

Meese

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Auditory neuropathy is a nosological term conceived to describe hearing impairment originating downstream from mechanoelectrical transduction and cochlear amplification of OHCs (40). The known mechanisms of auditory neuropathy include dysfunction of inner hair cells, the SGN, and the ribbon synapse, also known as synaptopathy (40). Our study indicates that ROR1 disruption leads to an auditory synaptopathy.…”

Section: Discussionmentioning

confidence: 67%

“…Deafness and conserved OAE in the studied family indicated auditory neuropathy, suggesting that ROR1 p.R736T mutation may also impair IHC innervation in humans. Auditory neuropathy is a nosological term conceived to describe hearing impairment originating downstream from mechanoelectrical transduction and cochlear amplification of OHCs (40). The known mechanisms of auditory neuropathy include dysfunction of inner hair cells, the SGN, and the ribbon synapse, also known as synaptopathy (40).…”

Section: Discussionmentioning

confidence: 99%

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

Diaz‐Horta

Abad

Sennaroḡlu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Hair cells of the inner ear, the mechanosensory receptors, convert sound waves into neural signals that are passed to the brain via the auditory nerve. Little is known about the molecular mechanisms that govern the development of hair cell-neuronal connections. We ascertained a family with autosomal recessive deafness associated with a common cavity inner ear malformation and auditory neuropathy. Via whole-exome sequencing, we identified a variant (c.2207G>C, p.R736T) in ROR1 (receptor tyrosine kinase-like orphan receptor 1), cosegregating with deafness in the family and absent in ethnicitymatched controls. ROR1 is a tyrosine kinase-like receptor localized at the plasma membrane. At the cellular level, the mutation prevents the protein from reaching the cellular membrane. In the presence of WNT5A, a known ROR1 ligand, the mutated ROR1 fails to activate NF-κB. Ror1 is expressed in the inner ear during development at embryonic and postnatal stages. We demonstrate that Ror1 mutant mice are severely deaf, with preserved otoacoustic emissions. Anatomically, mutant mice display malformed cochleae. Axons of spiral ganglion neurons show fasciculation defects. Type I neurons show impaired synapses with inner hair cells, and type II neurons display aberrant projections through the cochlear sensory epithelium. We conclude that Ror1 is crucial for spiral ganglion neurons to innervate auditory hair cells. Impairment of ROR1 function largely affects development of the inner ear and hearing in humans and mice.deafness | whole-exome sequencing | inner ear | innervation | NF-κB S ensorineural hearing loss (SNHL) is diagnosed in approximately 1 per 500 newborns (1). A genetic etiology is present in more than half of the cases. Inner ear anomalies (IEAs), demonstrated with computerized tomography or magnetic resonance imaging, are associated with SNHL in about one-third of individuals (2). Although IEAs can be diagnosed in patients with other clinical manifestations, such as those seen in Waardenburg [Mendelian Inheritance in Man (MIM) 193500], Pendred (MIM 274600), or BOR (MIM 113650) syndromes, the majority of cases fall into the category of nonsyndromic deafness. Despite recent progress in identifying genes that determine many forms of hearing loss (hereditaryhearingloss.org/), the genetic basis of IEAs in humans remains largely unknown.The inner ear is a complex organ that is built from a simple structure, referred to as the otocyst, through a series of morphogenetic events. Roughly, it consists of a dorsal vestibular and a ventral auditory component (3). Studies in model organisms have identified a number of genes that play roles in proper development of the inner ear. Mouse models have been particularly relevant because the anatomy and physiology of the murine auditory system are similar to those of humans. Mutations in human orthologs of many of these genes have been reported to cause deafness in humans as well (4).Next-generation sequencing technologies have allowed rapid identification of novel human deafness genes. Appro...

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“…2 ). In humans, the absolute latencies and supra-threshold amplitudes of waves, ABR wave I (distal peripheral portion of the AN [90] ), ABR wave III (fibers from cochlear nucleus to caudal auditory pons and superior olivary complex [91] ), ABR wave VI (medial geniculate body or the auditory thalamus), or ARB wave V (believed to correspond with the IC in the midbrain [92,93] ) can be analyzed for various stimulus intensity levels and, for example, recording time of ABR measurements that should be set at >10 ms. An increasing body of evidence demonstrates that, due to altered leisure behavior and demographic crisis, the hidden hearing loss and auditory neuropathy are likely widely prevalent over time [94][95][96] , contributing to presbycusis [62,64,97] or hyperacusis and tinnitus [21,22,98] .…”

Section: Functional Biomarker For An Fiber Responses: Abr Wave Fine Smentioning

confidence: 99%

Biomarkers for Hearing Dysfunction: Facts and Outlook

Rüttiger

Zimmermann

Knipper³

2017

ORL

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In medicine, biomarkers are a metric for disease state. More generally, a biomarker is anything that can be used as an indicator for a particular disease state or any physiological state of an organism. Here, we introduce functional and molecular biomarkers that are useful for categorizing defined subtypes of hearing disorder, which can help to selectively trace a particular dysfunction of the inner ear and the auditory pathway to disease.

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Auditory neuropathy — neural and synaptic mechanisms

Cited by 246 publications

References 140 publications

Ca ²⁺ -binding protein 2 inhibits Ca ²⁺ -channel inactivation in mouse inner hair cells

Ca ²⁺ -binding protein 2 inhibits Ca ²⁺ -channel inactivation in mouse inner hair cells

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

Biomarkers for Hearing Dysfunction: Facts and Outlook

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Auditory neuropathy — neural and synaptic mechanisms

Cited by 246 publications

References 140 publications

Ca 2+ -binding protein 2 inhibits Ca 2+ -channel inactivation in mouse inner hair cells

Ca 2+ -binding protein 2 inhibits Ca 2+ -channel inactivation in mouse inner hair cells

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

Biomarkers for Hearing Dysfunction: Facts and Outlook

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Product

Resources

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Ca ²⁺ -binding protein 2 inhibits Ca ²⁺ -channel inactivation in mouse inner hair cells

Ca ²⁺ -binding protein 2 inhibits Ca ²⁺ -channel inactivation in mouse inner hair cells