Auditory neuropathy — neural and synaptic mechanisms

Key Points

  • Auditory neuropathy impairs speech comprehension severely, beyond the extent that would be expected on the basis of increased threshold of audibility

  • Auditory neuropathy encompasses a range of disease mechanisms that typically disrupt the synaptic encoding and/or neural transmission of auditory information in the cochlea and auditory nerve

  • Auditory synaptopathy, impaired sound encoding at the synapses between inner hair cells and spiral ganglion neurons, results from genetic defects or insults such as exposure to loud noise

  • Advanced physiological and psychophysical testing combined with molecular genetic analysis facilitate diagnostics of auditory synaptopathy and neuropathy

  • Although traditional hearing aids often do not provide substantial benefit for patients with auditory synaptopathy or neuropathy, cochlear implants can provide effective hearing rehabilitation depending on the site(s) of disorder

Abstract

Sensorineural hearing impairment is the most common form of hearing loss, and encompasses pathologies of the cochlea and the auditory nerve. Hearing impairment caused by abnormal neural encoding of sound stimuli despite preservation of sensory transduction and amplification by outer hair cells is known as 'auditory neuropathy'. This term was originally coined for a specific type of hearing impairment affecting speech comprehension beyond changes in audibility: patients with this condition report that they “can hear but cannot understand”. This type of hearing impairment can be caused by damage to the sensory inner hair cells (IHCs), IHC ribbon synapses or spiral ganglion neurons. Human genetic and physiological studies, as well as research on animal models, have recently shown that disrupted IHC ribbon synapse function — resulting from genetic alterations that affect presynaptic glutamate loading of synaptic vesicles, Ca2+ influx, or synaptic vesicle exocytosis — leads to hearing impairment termed 'auditory synaptopathy'. Moreover, animal studies have demonstrated that sound overexposure causes excitotoxic loss of IHC ribbon synapses. This mechanism probably contributes to hearing disorders caused by noise exposure or age-related hearing loss. This Review provides an update on recently elucidated sensory, synaptic and neural mechanisms of hearing impairment, their corresponding clinical findings, and discusses current rehabilitation strategies as well as future therapies.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Clinical neurophysiology for definitive diagnosis of auditory neuropathy.
Figure 2: Disorders affecting inner hair cells (IHCs), their afferent synapses or spiral ganglion neurons (SGNs) degrade the neural representation of sound.
Figure 3: The afferent ribbon synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs).
Figure 4: Otoferlin has an essential role at the inner hair cell (IHC) ribbon synapse.
Figure 5: Hair cells use the vesicular glutamate transporter 3 to load synaptic vesicles with glutamate.
Figure 6: Irreversible loss of inner hair cell (IHC) ribbon synapses during exposure to loud noise in mice.

References

  1. 1

    World Health Organization. Primary ear and hearing care training resource. Advanced level. [online], (2006).

  2. 2

    Starr, A., Picton, T. W., Sininger, Y., Hood, L. J. & Berlin, C. I. Auditory neuropathy. Brain 119, 741–754 (1996). Starr and colleagues first coined the term 'auditory neuropathy' and provided a detailed auditory phenotype for hereditary sensory and motor neuropathy.

    Article  PubMed  Google Scholar 

  3. 3

    Zeng, F.-G., Kong, Y.-Y., Michalewski, H. J. & Starr, A. Perceptual consequences of disrupted auditory nerve activity. J. Neurophysiol. 93, 3050–3063 (2005).

    Article  PubMed  Google Scholar 

  4. 4

    Moser, T. et al. Diagnostik und therapie der auditorischen synaptopathie/neuropathie. HNO 54, 833–841 (in German) (2006).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Sutton, G. J. et al. Assessment and management of auditory neuropathy/auditory dys-synchrony: a recommended protocol. Newborn Hearing Screening Programme England) [online], (2004).

    Google Scholar 

  6. 6

    Starr, A., Zeng, F. G., Michalewski, H. J. & Moser, T. in The Senses: A Comprehensive Reference Vol 3. Ch. 23 (eds Basbaum, A. I. et al.) 397–412 (Academic Press, 2008).

    Google Scholar 

  7. 7

    Penido, R. C. & Isaac, M. L. Prevalence of auditory neuropathy spectrum disorder in an auditory health care service. Braz. J. Otorhinolaryngol. 79, 429–433 (2013).

    Article  PubMed  Google Scholar 

  8. 8

    Rance, G. et al. Clinical findings for a group of infants and young children with auditory neuropathy. Ear Hear. 20, 238–252 (1999).

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Foerst, A. et al. Prevalence of auditory neuropathy/synaptopathy in a population of children with profound hearing loss. Int. J. Pediatr. Otorhinolaryngol. 70, 1415–1422 (2006).

    Article  PubMed  Google Scholar 

  10. 10

    Rodríguez-Ballesteros, M. et al. A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy. Hum. Mutat. 29, 823–831 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. 11

    Thirlwall, A. S., Brown, D. J., McMillan, P. M., Barker, S. E. & Lesperance, M. M. Phenotypic characterization of hereditary hearing impairment linked to DFNA25. Arch. Otolaryngol. Head Neck Surg. 129, 830–835 (2003).

    Article  PubMed  Google Scholar 

  12. 12

    Matthews, G. & Fuchs, P. The diverse roles of ribbon synapses in sensory neurotransmission. Nat. Rev. Neurosci. 11, 812–822 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Bech-Hansen, N. T. et al. Loss-of-function mutations in a calcium-channel α1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness. Nat. Genet. 19, 264–267 (1998).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Strom, T. M. et al. An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nat. Genet. 19, 260–263 (1998).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Zeitz, C. et al. Mutations in CABP4, the gene encoding the Ca2+-binding protein 4, cause autosomal recessive night blindness. Am. J. Hum. Genet. 79, 657–667 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Khimich, D. et al. Hair cell synaptic ribbons are essential for synchronous auditory signalling. Nature 434, 889–894 (2005). Using mouse mutants with inner hair cell synapses deficient in the scaffold protein Bassoon and the synaptic ribbon, Khimich et al . demonstrated how high rates of presynaptic vesicle exocytosis are required for synchronous activation of the spiral ganglion neurons, reflected by the compound action potential.

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Buran, B. N. et al. Onset coding is degraded in auditory nerve fibers from mutant mice lacking synaptic ribbons. J. Neurosci. 30, 7587–7597 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Jung, S. et al. Disruption of adaptor protein 2 (AP-2) in cochlear hair cells impairs vesicle reloading of synaptic release sites and hearing. EMBO J. 34, 2686–2702 (2015). Near-complete restoration of hearing in a knockout mouse model of auditory synaptopathy by a postnatal gene transfer via injection of a viral vector into the cochlea.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Pangrsic, T. et al. Hearing requires otoferlin-dependent efficient replenishment of synaptic vesicles in hair cells. Nat. Neurosci. 13, 869–876 (2010). This study demonstrated that reduced otoferlin levels disrupt vesicle replenishment and, therefore, impair indefatigable transmitter release from inner hair cells.

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Parkinson, N. J. et al. Mutant β-spectrin 4 causes auditory and motor neuropathies in quivering mice. Nat. Genet. 29, 61–65 (2001).

    CAS  Article  PubMed  Google Scholar 

  21. 21

    Lacas-Gervais, S. et al. βIVΣ1 spectrin stabilizes the nodes of Ranvier and axon initial segments. J. Cell Biol. 166, 983–990 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Wichmann, C. & Moser, T. Relating structure and function of inner hair cell ribbon synapses. Cell Tissue Res. 361, 95–114 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Fuchs, P. A. Time and intensity coding at the hair cell's ribbon synapse. J. Physiol. 566, 7–12 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Moser, T., Neef, A. & Khimich, D. Mechanisms underlying the temporal precision of sound coding at the inner hair cell ribbon synapse. J. Physiol. 576, 55–62 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Pangrs˘ic˘, T., Reisinger, E. & Moser, T. Otoferlin: a multi-C2 domain protein essential for hearing. Trends Neurosci. 35, 671–680 (2012). A review of the molecular physiology of inner hair cell ribbon synapses, with a focus on otoferlin.

    Article  CAS  Google Scholar 

  26. 26

    Nouvian, R. et al. Exocytosis at the hair cell ribbon synapse apparently operates without neuronal SNARE proteins. Nat. Neurosci. 14, 411–413 (2011).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Strenzke, N. et al. Complexin-I is required for high-fidelity transmission at the endbulb of held auditory synapse. J. Neurosci. 29, 7991–8004 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Uthaiah, R. C. & Hudspeth, A. J. Molecular anatomy of the hair cell's ribbon synapse. J. Neurosci. 30, 12387–12399 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Vogl, C. et al. Unconventional molecular regulation of synaptic vesicle replenishment in cochlear inner hair cells. J. Cell. Sci. 128, 638–644 (2015).

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Roux, I. et al. Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse. Cell 127, 277–289 (2006). This study describes the auditory phenotype of otoferlin knockout mice and demonstrates that otoferlin has an essential role in inner hair cell exocytosis.

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Seal, R. P. et al. Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3. Neuron 57, 263–275 (2008). This Slc17a8 -knockout mouse study demonstrated that VGluT3 has an essential role in sound encoding at the inner hair cell ribbon synapse.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Ruel, J. et al. Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice. Am. J. Hum. Genet. 83, 278–292 (2008). This study revealed that a mutation in Vglut3 underlies autosomal dominant deafness-25 and showed the requirement of VGluT3 in sound encoding at the inner hair cell ribbon synapse.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Platzer, J. et al. Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels. Cell 102, 89–97 (2000).

    CAS  Article  PubMed  Google Scholar 

  34. 34

    Brandt, A., Striessnig, J. & Moser, T. Cav1. 3 channels are essential for development and presynaptic activity of cochlear inner hair cells. J. Neurosci. 23, 10832–10840 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Geisler, C. D. From Sound to Synapse: Physiology of the Mammalian Ear (Oxford Univ. Press, 1998).

    Google Scholar 

  36. 36

    Rutherford, M. A. & Moser, T. in The Primary Auditory Neurons of the Mammalian Cochlea (eds Dabdoub, A. et al.) 117–156 (Springer-Verlag, 2016). This book chapter is part of a recently published textbook on spiral ganglion neurons, and provides a comprehensive overview on the inner hair cell–spiral ganglion neuron synapse.

    Google Scholar 

  37. 37

    Mo, Z. L., Adamson, C. L. & Davis, R. L. Dendrotoxin-sensitive K+ currents contribute to accommodation in murine spiral ganglion neurons. J. Physiol. 542, 763 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Rutherford, M. A., Chapochnikov, N. M. & Moser, T. Spike encoding of neurotransmitter release timing by spiral ganglion neurons of the cochlea. J. Neurosci. 32, 4773–4789 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Glowatzki, E. & Fuchs, P. A. Transmitter release at the hair cell ribbon synapse. Nat. Neurosci. 5, 147–154 (2002). The first postsynaptic patch-clamp recording from the inner hair cell ribbon synapse of the rat demonstrates massive heterogeneity in size and shape of the excitatory postsynaptic currents, interpreted to reflect synchronous release of multiple vesicles despite the absence of a presynaptic action potential.

    CAS  Article  PubMed  Google Scholar 

  40. 40

    Chapochnikov, N. M. et al. Uniquantal release through a dynamic fusion pore is a candidate mechanism of hair cell exocytosis. Neuron 17, 1389–1403 (2014).

    Article  CAS  Google Scholar 

  41. 41

    Hossain, W. A., Antic, S. D., Yang, Y., Rasband, M. N. & Morest, D. K. Where is the spike generator of the cochlear nerve? Voltage-gated sodium channels in the mouse cochlea. J. Neurosci. 25, 6857–6868 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Yasunaga, S. et al. A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness. Nat. Genet. 21, 363–369 (1999).

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Varga, R. et al. OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele. J. Med. Genet. 43, 576–581 (2006).

    CAS  Article  PubMed  Google Scholar 

  44. 44

    Marlin, S. et al. Temperature-sensitive auditory neuropathy associated with an otoferlin mutation: deafening fever! Biochem. Biophys. Res. Commun. 394, 737–742 (2010).

    CAS  Article  PubMed  Google Scholar 

  45. 45

    Wang, D.-Y. et al. Screening mutations of OTOF gene in Chinese patients with auditory neuropathy, including a familial case of temperature-sensitive auditory neuropathy. BMC Med. Genet. 11, 79 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Romanos, J. et al. Novel OTOF mutations in Brazilian patients with auditory neuropathy. J. Hum. Genet. 54, 382–385 (2009).

    CAS  Article  PubMed  Google Scholar 

  47. 47

    Matsunaga, T. et al. A prevalent founder mutation and genotype–phenotype correlations of OTOF in Japanese patients with auditory neuropathy. Clin. Genet. 82, 425–432 (2012).

    CAS  Article  PubMed  Google Scholar 

  48. 48

    McNeil, P. L. & Kirchhausen, T. An emergency response team for membrane repair. Nat. Rev. Mol. Cell. Biol. 6, 499–505 (2005).

    CAS  Article  PubMed  Google Scholar 

  49. 49

    Liu, J. et al. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat. Genet. 20, 31–36 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Bansal, D. et al. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423, 168–172 (2003).

    CAS  Article  PubMed  Google Scholar 

  51. 51

    Jiménez, J. L. & Bashir, R. In silico functional and structural characterisation of ferlin proteins by mapping disease-causing mutations and evolutionary information onto three-dimensional models of their C2 domains. J. Neurol. Sci. 260, 114–123 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. 52

    Johnson, C. P. & Chapman, E. R. Otoferlin is a calcium sensor that directly regulates SNARE-mediated membrane fusion. J. Cell Biol. 191, 187–197 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Padmanarayana, M. et al. Characterization of the lipid binding properties of Otoferlin reveals specific interactions between PI(4,5)P2 and the C2C and C2F domains. Biochemistry 53, 5023–5033 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Ramakrishnan, N. A., Drescher, M. J. & Drescher, D. G. Direct interaction of otoferlin with syntaxin 1A, SNAP-25, and the L-type voltage-gated calcium channel Cav1.3. J. Biol. Chem. 284, 1364–1372 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Helfmann, S. et al. The crystal structure of the C2A domain of otoferlin reveals an unconventional top loop region. J. Mol. Biol. 406, 479–490 (2011).

    CAS  Article  PubMed  Google Scholar 

  56. 56

    Fuson, K. et al. Alternate splicing of dysferlin C2A confers Ca2+-dependent and Ca2+-independent binding for membrane repair. Structure 22, 104–115 (2014).

    CAS  Article  PubMed  Google Scholar 

  57. 57

    Santarelli, R., del Castillo, I., Cama, E., Scimemi, P. & Starr, A. Audibility, speech perception and processing of temporal cues in ribbon synaptic disorders due to OTOF mutations. Hear. Res. 330 (Pt B), 200–212 (2015).

    Article  PubMed  Google Scholar 

  58. 58

    Reisinger, E. et al. Probing the functional equivalence of otoferlin and synaptotagmin 1 in exocytosis. J. Neurosci. 31, 4886–4895 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59

    Dulon, D., Safieddine, S., Jones, S. M. & Petit, C. Otoferlin is critical for a highly sensitive and linear calcium-dependent exocytosis at vestibular hair cell ribbon synapses. J. Neurosci. 29, 10474–10487 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Varga, R. et al. Non-syndromic recessive auditory neuropathy is the result of mutations in the otoferlin (OTOF) gene. J. Med. Genet. 40, 45–50 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Schwander, M. et al. A forward genetics screen in mice identifies recessive deafness traits and reveals that pejvakin is essential for outer hair cell function. J. Neurosci. 27, 2163–2175 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Wynne, D. P. et al. Loudness adaptation accompanying ribbon synapse and auditory nerve disorders. Brain 136, 1626–1638 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  63. 63

    Duncker, S. V. et al. Otoferlin couples to clathrin-mediated endocytosis in mature cochlear inner hair cells. J. Neurosci. 33, 9508–9519 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    Greene, C. C. et al. DFNA25, a novel locus for dominant nonsyndromic hereditary hearing impairment, maps to 12q21-24. Am. J. Hum. Genet. 68, 254–260 (2001).

    CAS  Article  PubMed  Google Scholar 

  65. 65

    Obholzer, N. et al. Vesicular glutamate transporter 3 is required for synaptic transmission in zebrafish hair cells. J. Neurosci. 28, 2110–2118 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    Petek, E. et al. Molecular characterization of a 12q22-q24 deletion associated with congenital deafness: confirmation and refinement of the DFNA25 locus. Am. J. Med. Genet. A 117A, 122–126 (2003).

    Article  PubMed  Google Scholar 

  67. 67

    Baig, S. M. et al. Loss of Cav1.3 (CACNA1D) function in a human channelopathy with bradycardia and congenital deafness. Nat. Neurosci. 14, 77–84 (2011). The first report of a human deafness syndrome attributed to a loss-of-function mutation in CACNA1D.

    CAS  Article  PubMed  Google Scholar 

  68. 68

    Surmeier, D. J. Calcium, ageing, and neuronal vulnerability in Parkinson's disease. Lancet Neurol. 6, 933–938 (2007).

    CAS  Article  PubMed  Google Scholar 

  69. 69

    McKinney, B. C. & Murphy, G. G. The L-Type voltage-gated calcium channel Cav1.3 mediates consolidation, but not extinction, of contextually conditioned fear in mice. Learn. Mem. 13, 584–589 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Neef, J. et al. The Ca2+ channel subunit β2 regulates Ca2+ channel abundance and function in inner hair cells and is required for hearing. J. Neurosci. 29, 10730 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    Wycisk, K. A. et al. Mutation in the auxiliary calcium-channel subunit CACNA2D4 causes autosomal recessive cone dystrophy. Am. J. Hum. Genet. 79, 973–977 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Schrauwen, I. et al. A mutation in CABP2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment. Am. J. Hum. Genet. 91, 636–645 (2012). A report of a hearing impairment in a family with a CABP2 mutation, suggesting that inner hair cell synaptic dysfunction is caused by impaired presynaptic Ca2+ influx.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Haeseleer, F. et al. Essential role of Ca2+-binding protein 4, a Cav1.4 channel regulator, in photoreceptor synaptic function. Nat. Neurosci. 7, 1079–1087 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74

    Santarelli, R. et al. OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation. Brain 138, 563–576 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Yu-Wai-Man, P. et al. Multi-system neurological disease is common in patients with OPA1 mutations. Brain 133, 771–786 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    La Morgia, C., Carbonelli, M., Barboni, P., Sadun, A. A. & Carelli, V. Medical management of hereditary optic neuropathies. Front. Neurol. 5, 141 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Alexander, C. et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat. Genet. 26, 211–215 (2000).

    CAS  Article  PubMed  Google Scholar 

  78. 78

    Delettre, C. et al. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat. Genet. 26, 207–210 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Kasahara, A. & Scorrano, L. Mitochondria: from cell death executioners to regulators of cell differentiation. Trends Cell Biol. 24, 761–770 (2014).

    CAS  Article  PubMed  Google Scholar 

  80. 80

    Ferré, M. et al. Molecular screening of 980 cases of suspected hereditary optic neuropathy with a report on 77 novel OPA1 mutations. Hum. Mutat. 30, E692–E705 (2009).

    Article  PubMed  Google Scholar 

  81. 81

    Alavi, M. V. et al. A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy. Brain 130, 1029–1042 (2006).

    Article  Google Scholar 

  82. 82

    Starr, A., Dong, C. J. & Michalewski, H. J. Brain potentials before and during memory scanning. Electroencephalogr. Clin. Neurophysiol. 99, 28–37 (1996).

    CAS  Article  PubMed  Google Scholar 

  83. 83

    Starr, A. Pathology and physiology of auditory neuropathy with a novel mutation in the MPZ gene (Tyr145→Ser). Brain 126, 1604–1619 (2003).

    Article  PubMed  Google Scholar 

  84. 84

    Kabzin´ska, D. et al. Late-onset Charcot−Marie−Tooth type 2 disease with hearing impairment associated with a novel Pro105Thr mutation in the MPZ gene. Am. J. Med. Genet. A 143A, 2196–2199 (2007).

    Article  CAS  Google Scholar 

  85. 85

    Verhagen, W. I. M. et al. Sensorineural hearing impairment in patients with Pmp22 duplication, deletion, and frameshift mutations. Otol. Neurotol. 26, 405–414 (2005).

    CAS  Article  PubMed  Google Scholar 

  86. 86

    Kovach, M. J. et al. Anticipation in a unique family with Charcot−Marie−Tooth syndrome and deafness: delineation of the clinical features and review of the literature. Am. J. Med. Genet. 108, 295–303 (2002).

    CAS  Article  PubMed  Google Scholar 

  87. 87

    Rance, G. & Starr, A. Pathophysiological mechanisms and functional hearing consequences of auditory neuropathy. Brain 138, 3141–3158 (2015). In this review, Rance and Starr provide a comprehensive overview of spiral ganglion disorders and their clinical manifestations.

    Article  PubMed  Google Scholar 

  88. 88

    Delmaghani, S. et al. Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy. Nat. Genet. 38, 770–778 (2006).

    CAS  Article  PubMed  Google Scholar 

  89. 89

    Borck, G. et al. High frequency of autosomal-recessive DFNB59 hearing loss in an isolated Arab population in Israel. Clin. Genet. 82, 271–276 (2012).

    CAS  Article  PubMed  Google Scholar 

  90. 90

    Ebermann, I. et al. Truncating mutation of the DFNB59 gene causes cochlear hearing impairment and central vestibular dysfunction. Hum. Mutat. 28, 571–577 (2007).

    CAS  Article  PubMed  Google Scholar 

  91. 91

    Hashemzadeh Chaleshtori, M. et al. Novel mutations in the pejvakin gene are associated with autosomal recessive non-syndromic hearing loss in Iranian families. Clin. Genet. 72, 261–263 (2007).

    CAS  Article  PubMed  Google Scholar 

  92. 92

    Collin, R. W. J. et al. Involvement of DFNB59 mutations in autosomal recessive nonsyndromic hearing impairment. Hum. Mutat. 28, 718–723 (2007).

    CAS  Article  PubMed  Google Scholar 

  93. 93

    Delmaghani, S. et al. Hypervulnerability to sound exposure through impaired adaptive proliferation of peroxisomes. Cell 163, 894–906 (2015). This study demonstrated that genetic disruption of pevjakin increases vulnerability of hair cells and neurons to noise exposure, providing an interesting experimental model for hearing impairment as a multifactorial disease.

    CAS  Article  PubMed  Google Scholar 

  94. 94

    Kim, T. B. et al. A gene responsible for autosomal dominant auditory neuropathy (AUNA1) maps to 13q14–21. J. Med. Genet. 41, 872 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Starr, A. et al. A dominantly inherited progressive deafness affecting distal auditory nerve and hair cells. J. Assoc. Res. Otolaryngol. 5, 411–426 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  96. 96

    Schoen, C. J. et al. Increased activity of Diaphanous homolog 3 (DIAPH3)/diaphanous causes hearing defects in humans with auditory neuropathy and in Drosophila. Proc. Natl Acad. Sci. USA 107, 13396–13401 (2010).

    CAS  Article  PubMed  Google Scholar 

  97. 97

    Schoen, C. J., Burmeister, M. & Lesperance, M. M. Diaphanous homolog 3 (Diap3) overexpression causes progressive hearing loss and inner hair cell defects in a transgenic mouse model of human deafness. PLoS ONE 8, e56520 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98

    Rance, G. et al. Speech perception ability in individuals with Friedreich ataxia. Brain 131, 2002–2012 (2008).

    Article  PubMed  Google Scholar 

  99. 99

    Kirkim, G., Serbetcioglu, B., Erdag, T. K. & Ceryan, K. The frequency of auditory neuropathy detected by universal newborn hearing screening program. Int. J. Pediatr. Otorhinolaryngol. 72, 1461–1469 (2008).

    Article  PubMed  Google Scholar 

  100. 100

    Schulman-Galambos, C. & Galambos, R. Brain stem evoked response audiometry in newborn hearing screening. Arch. Otolaryngol. 105, 86–90 (1979).

    CAS  Article  PubMed  Google Scholar 

  101. 101

    Oh, W. et al. Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants. Pediatrics 112, 773–779 (2003).

    Article  PubMed  Google Scholar 

  102. 102

    Olds, C. & Oghalai, J. S. Audiologic impairment associated with bilirubin-induced neurologic damage. Semin. Fetal Neonatal Med. 20, 42–46 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  103. 103

    Smith, C. M., Barnes, G. P., Jacobson, C. A. & Oelberg, D. G. Auditory brainstem response detects early bilirubin neurotoxicity at low indirect bilirubin values. J. Perinatol. 24, 730–732 (2004).

    Article  PubMed  Google Scholar 

  104. 104

    Amatuzzi, M. G. et al. Selective inner hair cell loss in premature infants and cochlea pathological patterns from neonatal intensive care unit autopsies. Arch. Otolaryngol. Head Neck Surg. 127, 629–636 (2001).

    CAS  Article  PubMed  Google Scholar 

  105. 105

    Uziel, A., Marot, M. & Pujol, R. The Gunn rat: an experimental model for central deafness. Acta Otolaryngol. 95, 651–656 (1983).

    CAS  Article  PubMed  Google Scholar 

  106. 106

    Haustein, M. D. et al. Acute hyperbilirubinaemia induces presynaptic neurodegeneration at a central glutamatergic synapse. J. Physiol. 588, 4683–4693 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    Spencer, R. F., Shaia, W. T., Gleason, A. T., Sismanis, A. & Shapiro, S. M. Changes in calcium-binding protein expression in the auditory brainstem nuclei of the jaundiced Gunn rat. Hear. Res. 171, 129–141 (2002).

    CAS  Article  PubMed  Google Scholar 

  108. 108

    Attias, J., Raveh, E., Aizer-Dannon, A., Bloch-Mimouni, A. & Fattal-Valevski, A. Auditory system dysfunction due to infantile thiamine deficiency: long-term auditory sequelae. Audiol. Neurootol. 17, 309–320 (2012).

    CAS  Article  PubMed  Google Scholar 

  109. 109

    Oishi, K. et al. Targeted disruption of Slc19a2, the gene encoding the high-affinity thiamin transporter Thtr-1, causes diabetes mellitus, sensorineural deafness and megaloblastosis in mice. Hum. Mol. Genet. 11, 2951–2960 (2002).

    CAS  Article  PubMed  Google Scholar 

  110. 110

    Liberman, M. C., Tartaglini, E., Fleming, J. C. & Neufeld, E. J. Deletion of SLC19A2, the high affinity thiamine transporter, causes selective inner hair cell loss and an auditory neuropathy phenotype. J. Assoc. Res. Otolaryngol. 7, 211–217 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Yang, C.-H., Schrepfer, T. & Schacht, J. Age-related hearing impairment and the triad of acquired hearing loss. Front. Cell. Neurosci. 9, 276 (2015). This article, part of a special review issue of Frontiers in Cellular Neuroscience , provides a detailed update on sensory hair cell death and studies aiming at inducing hair cell regeneration.

    PubMed  PubMed Central  Google Scholar 

  112. 112

    Henry, W. R. & Mulroy, M. J. Afferent synaptic changes in auditory hair cells during noise-induced temporary threshold shift. Hear. Res. 84, 81–90 (1995).

    CAS  Article  PubMed  Google Scholar 

  113. 113

    Puel, J. L., Pujol, R., Ladrech, S. & Eybalin, M. α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid electrophysiological and neurotoxic effects in the guinea-pig cochlea. Neuroscience 45, 63–72 (1991).

    CAS  Article  PubMed  Google Scholar 

  114. 114

    Puel, J. L., Ruel, J., Gervais d'Aldin, C. & Pujol, R. Excitotoxicity and repair of cochlear synapses after noise-trauma induced hearing loss. Neuroreport 9, 2109–2114 (1998).

    CAS  Article  PubMed  Google Scholar 

  115. 115

    Stamataki, S., Francis, H. W., Lehar, M., May, B. J. & Ryugo, D. K. Synaptic alterations at inner hair cells precede spiral ganglion cell loss in aging C57BL/6J mice. Hear. Res. 221, 104–118 (2006).

    Article  PubMed  Google Scholar 

  116. 116

    Kujawa, S. G. & Liberman, M. C. Adding insult to injury: cochlear nerve degeneration after 'temporary' noise-induced hearing loss. J. Neurosci. 29, 14077 (2009). This study shows that in mice, sound overexposure that only temporarily reduces audibility can cause a permanent loss of inner hair cell ribbon synapses and subsequent loss of spiral ganglion neurons.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117

    Sergeyenko, Y., Lall, K., Liberman, M. C. & Kujawa, S. G. Age-related cochlear synaptopathy: an early-onset contributor to auditory functional decline. J. Neurosci. 33, 13686–13694 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118

    Kujawa, S. G. & Liberman, M. C. Synaptopathy in the noise-exposed and aging cochlea: primary neural degeneration in acquired sensorineural hearing loss. Hear. Res. 330(Pt B), 191–199 (2015). This Review is a part of a review series on auditory synapses and synaptopathies and summarizes a large body of animal work on synaptic alterations in noise-induced and age-related hearing loss.

    Article  PubMed  PubMed Central  Google Scholar 

  119. 119

    Hakuba, N., Koga, K., Gyo, K., Usami, S. I. & Tanaka, K. Exacerbation of noise-induced hearing loss in mice lacking the glutamate transporter GLAST. J. Neurosci. 20, 8750–8753 (2000).

    CAS  Article  PubMed  Google Scholar 

  120. 120

    Meyer, A. C. et al. Tuning of synapse number, structure and function in the cochlea. Nat. Neurosci. 12, 444–453 (2009).

    CAS  Article  PubMed  Google Scholar 

  121. 121

    Furman, A. C., Kujawa, S. G. & Liberman, M. C. Noise-induced cochlear neuropathy is selective for fibers with low spontaneous rates. J. Neurophysiol. 110, 577–586 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  122. 122

    Bourien, J. et al. Contribution of auditory nerve fibers to compound action potential of the auditory nerve. J. Neurophysiol. 112, 1025–1039 (2014).

    CAS  Article  PubMed  Google Scholar 

  123. 123

    Wan, G., Gómez-Casati, M. E., Gigliello, A. R., Liberman, M. C. & Corfas, G. Neurotrophin-3 regulates ribbon synapse density in the cochlea and induces synapse regeneration after acoustic trauma. eLIFE 3, e03564 (2014).

    Article  CAS  PubMed Central  Google Scholar 

  124. 124

    Schaette, R. & McAlpine, D. Tinnitus with a normal audiogram: physiological evidence for hidden hearing loss and computational model. J. Neurosci. 31, 13452–13457 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 125

    Starr, A. et al. Absence of both auditory evoked potentials and auditory percepts dependent on timing cues. Brain 114, 1157–1180 (1991).

    Article  PubMed  Google Scholar 

  126. 126

    Starr, A. et al. Cochlear receptor (microphonic and summating potentials, otoacoustic emissions) and auditory pathway (auditory brain stem potentials) activity in auditory neuropathy. Ear Hear. 22, 91 (2001).

    CAS  Article  PubMed  Google Scholar 

  127. 127

    Santarelli, R. et al. Abnormal cochlear potentials from deaf patients with mutations in the otoferlin gene. J. Assoc. Res. Otolaryngol. 10, 545–556 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  128. 128

    Pauli-Magnus, D. et al. Detection and differentiation of sensorineural hearing loss in mice using auditory steady-state responses and transient auditory brainstem responses. Neuroscience 149, 673–684 (2007).

    CAS  Article  PubMed  Google Scholar 

  129. 129

    Shearer, A. E. & Smith, R. J. H. Massively parallel sequencing for genetic diagnosis of hearing loss: the new standard of care. Otolaryngol. Head Neck Surg. 153, 175–182 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  130. 130

    Dean, C., Felder, G. & Kim, A. H. Analysis of speech perception outcomes among patients receiving cochlear implants with auditory neuropathy spectrum disorder. Otol. Neurotol. 34, 1610–1614 (2013).

    Article  PubMed  Google Scholar 

  131. 131

    Humphriss, R. et al. Does cochlear implantation improve speech recognition in children with auditory neuropathy spectrum disorder? A systematic review. Int. J. Audiol. 52, 442–454 (2013).

    Article  PubMed  Google Scholar 

  132. 132

    Roush, P., Frymark, T., Venediktov, R. & Wang, B. Audiologic management of auditory neuropathy spectrum disorder in children: a systematic review of the literature. Am. J. Audiol. 20, 159–170 (2011).

    Article  PubMed  Google Scholar 

  133. 133

    Giraudet, F. & Avan, P. Auditory neuropathies: understanding their pathogenesis to illuminate intervention strategies. Curr. Opin. Neurol. 25, 50–56 (2012).

    Article  PubMed  Google Scholar 

  134. 134

    Rance, G. & Barker, E. J. Speech and language outcomes in children with auditory neuropathy/dys-synchrony managed with either cochlear implants or hearing aids. Int. J. Audiol. 48, 313–320 (2009).

    Article  PubMed  Google Scholar 

  135. 135

    Ching, T. Y. C. et al. Impact of the presence of auditory neuropathy spectrum disorder (ANSD) on outcomes of children at three years of age. Int. J. Audiol. 52, S55–S64 (2013).

    Article  PubMed  Google Scholar 

  136. 136

    Hall, R. D. Estimation of surviving spiral ganglion cells in the deaf rat using the electrically evoked auditory brainstem response. Hear. Res. 49, 155–168 (1990).

    CAS  Article  PubMed  Google Scholar 

  137. 137

    Hall, R. D. Estimation of surviving spiral ganglion cells in the deaf rat using the electrically evoked auditory brainstem response. Hear. Res. 45, 123–136 (1990).

    CAS  Article  PubMed  Google Scholar 

  138. 138

    Zhou, R., Abbas, P. J. & Assouline, J. G. Electrically evoked auditory brainstem response in peripherally myelin-deficient mice. Hear Res. 88, 98–106 (1995).

    CAS  Article  PubMed  Google Scholar 

  139. 139

    Rouillon, I. et al. Results of cochlear implantation in two children with mutations in the OTOF gene. Int. J. Pediatr. Otorhinolaryngol. 70, 689–696 (2006).

    CAS  Article  PubMed  Google Scholar 

  140. 140

    Hernandez, V. H. et al. Optogenetic stimulation of the auditory pathway. J. Clin. Invest. 124, 1114–1129 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Jeschke, M. & Moser, T. Considering optogenetic stimulation for cochlear implants. Hear. Res. 322, 224–234 (2015).

    Article  PubMed  Google Scholar 

  142. 142

    Akil, O. et al. Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy. Neuron 75, 283–293 (2012). This mouse study demonstrated a near-complete restoration of hearing in a knockout mouse model of auditory synaptopathy by a postnatal gene transfer via injection of a viral vector into the cochlea.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  143. 143

    US National Library of Medicine. ClinicalTrials.gov[online] (2015).

Download references

Acknowledgements

The authors would like to thank Drs Nicola Strenzke and Regis Nouvian for feedback on the manuscript, Dr Carolin Wichmann for the electron micrograph in Figure 3 and Dr Nouvian for providing artwork for Figures 3 and 4.

Author information

Affiliations

Authors

Contributions

Both authors researched the literature, assembled the Figures, and wrote, edited and revised the manuscript.

Corresponding author

Correspondence to Tobias Moser.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

PowerPoint slides

Glossary

Auditory neuropathy

A hearing impairment found in individuals with hereditary motor and sensory neuropathy; impairs speech comprehension beyond what would be expected on the basis of pure tone audiograms.

Ribbon synapses

Highly specialized synapses between the inner hair cells and spiral ganglion neurons, with an electron-dense structure — the synaptic ribbon — at the presynaptic active zone that mediates neurotransmitter release.

Cochlear microphone potentials

Outer hair cells generate local cochlear potentials that follow the sound stimulus so precisely that they are called 'microphone potentials'.

Otoacoustic emission

Sound generated from within the inner ear that can be measured with a sensitive microphone in the external ear canal to assess outer hair cell function.

Auditory brainstem responses

Evoked potentials in response to repetitive acoustic stimulation that are recorded from scalp EEG electrodes and typically have five peaks, referred to as waves I–V.

Spiral ganglion compound action potential

The first auditory brainstem response peak, wave I, reflects the spiral ganglion compound action potential; this potential can be recorded with better resolution using electrocochleography.

Auditory synaptopathy

Hearing impairment caused by dysfunction or loss of ribbon synapses in the inner hair cells; has been termed auditory synaptopathy and can show clinical findings similar to those described above for auditory neuropathy.

Organ of Corti

The organ of Corti is the end organ of the sense of hearing that harbours the sensory inner and outer hair cells, as well as afferent and efferent nerve fibres and various types of supporting cells.

Compound action potential

Reflects the synchronized firing of spiral ganglion neurons; assessed by intrameatal or transtympanic electrocochleography.

Glutamate excitotoxicity

Excessive presynaptic glutamate release leading to massive depolarization and subsequent synapse loss.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Moser, T., Starr, A. Auditory neuropathy — neural and synaptic mechanisms. Nat Rev Neurol 12, 135–149 (2016). https://doi.org/10.1038/nrneurol.2016.10

Download citation

Further reading

Search

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing