Guanylyl Cyclase A/cGMP Signaling Slows Hidden, Age- and Acoustic Trauma-Induced Hearing Loss

Marchetta, Philine; Möhrle, Dorit; Eckert, Philipp; Reimann, Katrin; Wolter, Steffen; Tolone, Arianna; Lang, Isabelle; Wolters, Markus; Feil, Robert; Engel, Jutta; Paquet-Durand, François; Kühn, Michaela; Knipper, Marlies; Rüttiger, Lukas

doi:10.3389/fnagi.2020.00083

Cited by 10 publications

(21 citation statements)

References 109 publications

(167 reference statements)

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“…To study the compensation mechanisms underlying age-related synaptopathy, we first compared the hearing thresholds between young (2.9–6.6 months, n = 54/27 ears/animals), middle-aged (9.4–14.3 months, n = 28/14 ears/animals), and old (15.3–22.5 months, 54/27 ears/animals) BLEV reporter mice. The ABR evoked by low frequency-containing (click), high frequency-containing (noise burst), and pure tone frequency-specific auditory stimuli were tested as described [ 35 ]. Old BLEV mice showed a significant increase in threshold compared with young and middle-aged animals measured by click-evoked ABR ( Figure 1 a; all statistical findings and details of the tests can be found in the figure legends and in Table 1 ), noise-burst stimuli ( Figure 1 b), and pure tone frequencies ( Figure 1 c).…”

Section: Resultsmentioning

confidence: 99%

Age-Dependent Auditory Processing Deficits after Cochlear Synaptopathy Depend on Auditory Nerve Latency and the Ability of the Brain to Recruit LTP/BDNF

et al. 2020

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Age-related decoupling of auditory nerve fibers from hair cells (cochlear synaptopathy) has been linked to temporal processing deficits and impaired speech recognition performance. The link between both is elusive. We have previously demonstrated that cochlear synaptopathy, if centrally compensated through enhanced input/output function (neural gain), can prevent age-dependent temporal discrimination loss. It was also found that central neural gain after acoustic trauma was linked to hippocampal long-term potentiation (LTP) and upregulation of brain-derived neurotrophic factor (BDNF). Using middle-aged and old BDNF-live-exon-visualization (BLEV) reporter mice we analyzed the specific recruitment of LTP and the activity-dependent usage of Bdnf exon-IV and -VI promoters relative to cochlear synaptopathy and central (temporal) processing. For both groups, specimens with higher or lower ability to centrally compensate diminished auditory nerve activity were found. Strikingly, low compensating mouse groups differed from high compensators by prolonged auditory nerve latency. Moreover, low compensators exhibited attenuated responses to amplitude-modulated tones, and a reduction of hippocampal LTP and Bdnf transcript levels in comparison to high compensators. These results suggest that latency of auditory nerve processing, recruitment of hippocampal LTP, and Bdnf transcription, are key factors for age-dependent auditory processing deficits, rather than cochlear synaptopathy or aging per se.

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Section: Resultsmentioning

confidence: 99%

Age-Dependent Auditory Processing Deficits after Cochlear Synaptopathy Depend on Auditory Nerve Latency and the Ability of the Brain to Recruit LTP/BDNF

et al. 2020

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“…Strikingly, when GC‐A was analysed in isolated mature hair cells, the expression was found to be restricted to outer hair cells and spiral ganglia but not inner hair cells (Figure 2a,b) (Marchetta, Möhrle, et al, 2020). Also, in agreement with previous studies, the RNA of GC‐A ligands ANP and BNP was observed in outer hair cells, spiral ganglia and inner hair cell (Dornhoffer et al, 2002; Marchetta, Möhrle, et al, 2020; Möhrle et al, 2017; Suzuki et al, 1998). When the hearing of GC‐A KO mice was analysed (Marchetta, Möhrle, et al, 2020), no profound effect on basic hearing function was observed, as also described for sGC KO mice (Möhrle et al, 2017).…”

Section: Role Of Gc‐a In Hearingmentioning

confidence: 99%

“…Thus, the hearing thresholds, when measured using distortion product otoacoustic emission as a metric for electromotile properties of outer hair cells (El‐Badry & McFadden, 2007; Rüttiger et al, 2017), were similar between WT and GC‐A KO mice for all young, middle aged and old GC‐A KO mice. Analysis of frequency‐specific thresholds of distortion product otoacoustic emission signals, however, revealed that outer hair cell‐specific responses at higher frequencies (11.3 kHz) were already reduced in young GC‐A KO mice and remaining constantly lower throughout all ages (Marchetta, Möhrle, et al, 2020). This suggested a role of GC‐A in maintaining the basic integrity of outer hair cells particular in high‐frequency cochlear turns.…”

Section: Role Of Gc‐a In Hearingmentioning

confidence: 99%

The role of cGMP signalling in auditory processing in health and disease

Marchetta

Rüttiger

Hobbs

et al. 2021

British J Pharmacology

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cGMP is generated by the cGMP-forming guanylyl cyclases (GCs), the intracellular nitric oxide (NO)-sensitive (soluble) guanylyl cyclase (sGC) and transmembrane GC (e.g. GC-A and GC-B). In summarizing the particular role of cGMP signalling for hearing, we show that GC generally do not interfere significantly with basic hearing function but rather sustain a healthy state for proper temporal coding, fast discrimination and adjustments during injury. sGC is critical for the integrity of the first synapse in the ascending auditory pathway, the inner hair cell synapse. GC-A promotes hair cell stability under stressful conditions such as acoustic trauma or ageing. GC-B plays a role in the development of efferent feed-back and gain control.Regarding the crucial role hearing has for language development, speech discrimination and cognitive brain functions, differential pharmaceutical targeting of GCs offers therapeutic promise for the restoration of hearing. K E Y W O R D S central auditory processing, guanylyl cyclases, hearing function, temporal coding | INTRODUCTIONWorldwide, hearing loss is considered to be the fourth leading cause of disability, which today, in industrialized countries, affects about 190 million people. The rising number of affected people in the younger population and the dramatic shift in societal demographics, will soon significantly increase the total number of people with hearing deficits. While hearing loss is not life-threatening, mid-age hearing disorder was recently shown to be a major risk factor for dementia (Livingston et al., 2017). Indeed, the prevention of hearing loss with age has been suggested as a major action on lowering the future prevalence of dementia (Montero-Odasso et al., 2020). While to date degeneration of the stria vascularis and its vasculature were considered to be a main cause of hearing loss with age (Fischer et al., 2020;Frisina & Frisina, 2013), previous studies suggested that damage to outer hair cells proceeds stria degeneration (Wu et al., 2019). Outer hair cells are electromotile and serve as a piezo-like motor in the inner ear to amplify the vibrations of the basilar membrane in the cochlea (Dallos & Harris, 1978). Gradual noise damage to outer hair cells over lifetime was labelled as a major contributor to hearing loss in humans (Wu et al., 2019).

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“…Acoustic noise exposure has been suggested to decrease the functionality of KCNQ4 on the surface membrane, thereby playing a pivotal role in noise-induced hearing loss. Loss of KCNQ4 on the membranes of OHCs in cochlear regions of high frequency was reported to precede the loss of OHCs in mouse models [ 44 , 52 ]. Likewise, KCNQ4 was also reported to be lost from the surface membrane of OHCs in cochlear regions of low frequency following exposure to low frequency noise [ 53 ].…”

Section: Association Of Kcnq4 and Noise-induced Hearing Lossmentioning

confidence: 99%

Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss

Rim

Choi

Jung

et al. 2021

IJMS

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Potassium voltage-gated channel subfamily q member 4 (KCNQ4) is a voltage-gated potassium channel that plays essential roles in maintaining ion homeostasis and regulating hair cell membrane potential. Reduction of the activity of the KCNQ4 channel owing to genetic mutations is responsible for nonsyndromic hearing loss, a typically late-onset, initially high-frequency loss progressing over time. In addition, variants of KCNQ4 have also been associated with noise-induced hearing loss and age-related hearing loss. Therefore, the discovery of small compounds activating or potentiating KCNQ4 is an important strategy for the curative treatment of hearing loss. In this review, we updated the current concept of the physiological role of KCNQ4 in the inner ear and the pathologic mechanism underlying the role of KCNQ4 variants with regard to hearing loss. Finally, we focused on currently developed KCNQ4 activators and their pros and cons, paving the way for the future development of specific KCNQ4 activators as a remedy for hearing loss.

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Guanylyl Cyclase A/cGMP Signaling Slows Hidden, Age- and Acoustic Trauma-Induced Hearing Loss

Cited by 10 publications

References 109 publications

Age-Dependent Auditory Processing Deficits after Cochlear Synaptopathy Depend on Auditory Nerve Latency and the Ability of the Brain to Recruit LTP/BDNF

Age-Dependent Auditory Processing Deficits after Cochlear Synaptopathy Depend on Auditory Nerve Latency and the Ability of the Brain to Recruit LTP/BDNF

The role of cGMP signalling in auditory processing in health and disease

Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss

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