Biomarkers for Hearing Dysfunction: Facts and Outlook

Rüttiger, Lukas; Zimmermann, Ulrike; Knipper, Marlies

doi:10.1159/000455705

Cited by 30 publications

(41 citation statements)

References 153 publications

(189 reference statements)

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“…OHC electromotility forms the basis of the sound-evoked neural potentials at threshold (Marcon and Patuzzi, 2008). To assess OHC function, we recorded ear canal sound pressure changes induced by distortion products of the otoacoustic emissions (DPOAEs) (Shera and Guinan, 1999) that are specifically generated upon intact electromechanical responses of OHCs (El-Badry and McFadden, 2007;Rüttiger et al, 2017). We analyzed the frequency-specific thresholds of DPOAE signals from amplitude input-output functions by presenting pure-tone sounds from f2 5 4-32 kHz and increasing sound level (L1 5 210-65 dB SPL) in NO-GC isoform-specific KO mice compared with age-matched WT mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The auditory stimulus-evoked ABR wave I (Fig. 3) reflects the summed activity of the auditory nerve fibers (Melcher and Kiang, 1996) and is a useful functional biomarker for auditory nerve degeneration after noise exposure (Rüttiger et al, 2017).…”

Section: Downloaded Frommentioning

confidence: 99%

“…In the present study, hearing function was analyzed for the first time in the previously generated NO-GC1 KO and NO-GC2 KO mice (Mergia et al, 2006). We compared the morphologic and functional biomarkers in these mice (Rüttiger et al, 2017). Specifically, the detection of surface expression of the potassium voltage-gated channel subfamily KQT member 4 (KCNQ4), which accounts for the predominant K 1 conductance (I K,n ) of mature OHCs (Marcotti and Kros, 1999), is used as a marker for OHCs (Winter et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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NO-Sensitive Guanylate Cyclase Isoforms NO-GC1 and NO-GC2 Contribute to Noise-Induced Inner Hair Cell Synaptopathy

et al. 2017

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Nitric oxide (NO) activates the NO-sensitive soluble guanylate cyclase (NO-GC, sGC) and triggers intracellular signaling pathways involving cGMP. For survival of cochlear hair cells and preservation of hearing, NO-mediated cascades have both protective and detrimental potential. Here we examine the cochlear function of mice lacking one of the two NO-sensitive guanylate cyclase isoforms [NO-GC1 knockout (KO) or NO-GC2 KO]. The deletion of NO-GC1 or NO-GC2 did not influence electromechanical outer hair cell (OHC) properties, as measured by distortion product otoacoustic emissions, neither before nor after noise exposure, nor were click- or noise-burst-evoked auditory brainstem response thresholds different from controls. Yet inner hair cell (IHC) ribbons and auditory nerve responses showed significantly less deterioration in NO-GC1 KO and NO-GC2 KO mice after noise exposure. Consistent with a selective role of NO-GC in IHCs, NO-GC 1 mRNA was found in isolated IHCs but not in OHCs. Using transgenic mice expressing the fluorescence resonance energy transfer-based cGMP biosensor cGi500, NO-induced elevation of cGMP was detected in real-time in IHCs but not in OHCs. Pharmacologic long-term treatment with a NO-GC stimulator altered auditory nerve responses but did not affect OHC function and hearing thresholds. Interestingly, NO-GC stimulation exacerbated the loss of auditory nerve response in aged animals but attenuated the loss in younger animals. We propose NO-GC2 and, to some degree, NO-GC1 as targets for early pharmacologic prevention of auditory fiber loss (synaptopathy). Both isoforms provide selective benefits for hearing function by maintaining the functional integrity of auditory nerve fibers in early life rather than at old age.

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Section: Resultsmentioning

confidence: 99%

Section: Downloaded Frommentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NO-Sensitive Guanylate Cyclase Isoforms NO-GC1 and NO-GC2 Contribute to Noise-Induced Inner Hair Cell Synaptopathy

et al. 2017

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“…Here, we observed that the variation of stress hormone levels in mature female rats correlated with a prominent variation in auditory nerve function for processing especially high‐frequency stimuli. These variations in responsiveness to sound occur independently of OHC function as assessed from DPOAEs (43) that define hearing thresholds via OHC electromotile response properties (23, 44, 45). We also did not observe any significant influence from pretreatment with the GC antagonist, mifepristone, or the mineralocorticoid antagonist, spironolactone, on hearing threshold 2–3 wk after nontraumatic (sham) or traumatic sound exposure (AT).…”

Section: Discussionmentioning

confidence: 99%

The glucocorticoid antagonist mifepristone attenuates sound‐induced long‐term deficits in auditory nerve response and central auditory processing in female rats

et al. 2018

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Systemic corticosteroids have been the mainstay of treatment for various hearing disorders for more than 30 yr. Accordingly, numerous studies have described glucocorticoids (GCs) and stressors to be protective in the auditory organ against damage associated with a variety of health conditions, including noise exposure. Conversely, stressors are also predictive risk factors for hearing disorders. How both of these contrasting stress actions are linked has remained elusive. Here, we demonstrate that higher corticosterone levels during acoustic trauma in female rats is highly correlated with a decline of auditory fiber responses in high-frequency cochlear regions, and that hearing thresholds and the outer hair cell functions (distortion products of otoacoustic emissions) are left unaffected. Moreover, when GC receptor (GR) or mineralocorticoid receptor (MR) activation was antagonized by mifepristone or spironolactone, respectively, GR, but not MR, inhibition significantly and permanently attenuated trauma-induced effects on auditory fiber responses, including inner hair cell ribbon loss and related reductions of early and late auditory brainstem responses. These findings strongly imply that higher corticosterone stress levels profoundly impair auditory nerve processing, which may influence central auditory acuity. These changes are likely GR mediated as they are prevented by mifepristone.-Singer, W., Kasini, K., Manthey, M., Eckert, P., Armbruster, P., Vogt, M. A., Jaumann, M., Dotta, M., Yamahara, K., Harasztosi, C., Zimmermann, U., Knipper, M., Rüttiger, L. The glucocorticoid antagonist mifepristone attenuates sound-induced long-term deficits in auditory nerve response and central auditory processing in female rats.

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“…DPOAEs induce IE-canal sound pressure changes (Shera & Guinan, 1999) that are specifically generated upon intact electromechanical responses of OHCs (El-Badry & McFadden, 2007;Rüttiger, Zimmermann, & Knipper, 2017). We analyzed the thresholds of DPOAE I/O functions of emission amplitudes evoked by f 2 = 4 to 32 kHz pure-tone sounds in GDNF mutant mice in comparison to age-matched control mice.…”

Section: Hearing Thresholds and Ohc Function Of Atoh1-cre-and Trkc-mentioning

confidence: 99%

Differential deletion of GDNF in the auditory system leads to altered sound responsiveness

Harasztosi

Wolter

Gutsche

et al. 2019

J of Neuroscience Research

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Glial‐derived neurotrophic factor (GDNF) has been proposed as a potent neurotrophic factor with the potential to cure neurodegenerative diseases. In the cochlea, GDNF has been detected in auditory neurons and sensory receptor cells and its expression is upregulated upon trauma. Moreover, the application of GDNF in different animal models of deafness has shown its capacity to prevent hearing loss and promoted its future use in therapeutic trials in humans. In the present study we have examined the endogenous requirement of GDNF during auditory development in mice. Using a lacZ knockin allele we have confirmed the expression of GDNF in the cochlea including its sensory regions during development. Global inactivation of GDNF throughout the hearing system using a Foxg1‐Cre line causes perinatal lethality but reveals no apparent defects during formation of the cochlea. Using TrkC‐Cre and Atoh1‐Cre lines, we were able to generate viable mutants lacking GDNF in auditory neurons or both auditory neurons and sensory hair cells. These mutants show normal frequency‐dependent auditory thresholds. However, mechanoelectrical response properties of outer hair cells (OHCs) in TrkC‐Cre GDNF mutants are altered at low thresholds. Furthermore, auditory brainstem wave analysis shows an abnormal increase of wave I. On the other hand, Atoh1‐Cre GDNF mutants show normal OHC function but their auditory brainstem wave pattern is reduced at the levels of wave I, III and IV. These results show that GDNF expression during the development is required to maintain functional hearing at different levels of the auditory system.

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Biomarkers for Hearing Dysfunction: Facts and Outlook

Cited by 30 publications

References 153 publications

NO-Sensitive Guanylate Cyclase Isoforms NO-GC1 and NO-GC2 Contribute to Noise-Induced Inner Hair Cell Synaptopathy

NO-Sensitive Guanylate Cyclase Isoforms NO-GC1 and NO-GC2 Contribute to Noise-Induced Inner Hair Cell Synaptopathy

The glucocorticoid antagonist mifepristone attenuates sound‐induced long‐term deficits in auditory nerve response and central auditory processing in female rats

Differential deletion of GDNF in the auditory system leads to altered sound responsiveness

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