Search

The pathogenic variants in KCNQ4 cause DFNA2 nonsyndromic hearing loss. However, the understanding of genotype–phenotype correlations between KCNQ4 and hearing is limited. Here, we identified a novel KCNQ4 mutation p.G228D from a Chinese family, including heterozygotes characterized by high‐frequency hearing loss that is progressive across all frequencies and homozygotes with more severe hearing loss. We constructed a novel murine model with humanized homologous Kcnq4 mutation. The heterozygotes had mid‐frequency and high‐frequency hearing loss at 4 weeks, and moved toward all frequencies hearing loss at 12 weeks, while the homozygotes had severe‐to‐profound hearing loss at 8 weeks. The degeneration of outer hair cells (OHCs) was observed from basal to apical turn of cochlea. The reduced K+ currents and depolarized resting potentials were revealed in OHCs. Remarkably, we observed the loss of inner hair cells (IHCs) in the region corresponding to the frequency above 32 kHz at 8–12 weeks. The results suggest the degeneration of OHCs and IHCs may contribute to high‐frequency hearing loss in DFNA2 over time. Our findings broaden the variants of KCNQ4 and provide a novel mouse model of progressive hearing loss, which contributes to an understanding of pathogenic mechanism and eventually treatment of DFNA2 progressive hearing loss. [ABSTRACT FROM AUTHOR]

C. Guo et al. (Hearing phenotypes of patients with hearing loss homozygous for the GJB2 c.235delc mutation) investigate the hearing phenotypes of 244 Chinese patients with hearing loss associated with the homozygous c.235delC mutation of GJB2 and report a significant variation in their binaural hearing loss phenotypes, including severity of hearing loss, and audiogram shapes. Although SNHL is induced by various factors through different approaches and mechanisms, the major cause for SNHL is irreversible loss of either inner ear hair cells (HCs) or degeneration of spiral ganglion neurons (SGNs). [Extracted from the article]

Hearing is an extremely delicate sense that is particularly vulnerable to insults from environment, including drugs and noise. Unsurprisingly, mice of different genetic backgrounds show different susceptibility to hearing loss. In particular, CBA/CaJ (CBA) mice maintain relatively stable hearing over age while C57BL/6J (B6) mice show a steady decline of hearing, making them a popular model for early onset hearing loss. To reveal possible underlying mechanisms, we examined cellular differences in the cochlea of these two mouse strains. Although the ABR threshold and Wave I latency are comparable between them, B6 mice have a smaller Wave I amplitude. This difference is probably due to fewer spiral ganglion neurons found in B6 mice, as the number of ribbon synapses per inner hair cell (IHC) is comparable between the two mouse strains. Next, we compared the outer hair cell (OHC) function and we found OHCs from B6 mice are larger in size but the prestin density is similar among them, consistent with the finding that they share similar hearing thresholds. Lastly, we examined the IHC function and we found IHCs from B6 mice have a larger Ca2+ current, release more synaptic vesicles and recycle synaptic vesicles more quickly. Taken together, our results suggest that excessive exocytosis from IHCs in B6 mice may raise the probability of glutamate toxicity in ribbon synapses, which could accumulate over time and eventually lead to early onset hearing loss. [ABSTRACT FROM AUTHOR]

Summary Sound-evoked spikes in the auditory nerve can phase-lock with submillisecond precision for prolonged periods of time. However, the synaptic mechanisms that enable this accurate spike firing remain poorly understood. Using paired recordings from adult frog hair cells and their afferent fibers, we show here that during sine-wave stimuli, synaptic failures occur even during strong stimuli. However, exclusion of these failures leads to mean excitatory postsynaptic current (EPSC) amplitudes that are independent of Ca 2+ current. Given the intrinsic jitter in spike triggering, evoked synaptic potentials and spikes had surprisingly similar degrees of synchronization to a sine-wave stimulus. This similarity was explained by an unexpected finding: large-amplitude evoked EPSCs have a significantly larger synchronization index than smaller evoked EPSCs. Large EPSCs therefore enhance the precision of spike timing. The hair cells’ unique capacity for continuous, large-amplitude, and highly synchronous multiquantal release thus underlies its ability to trigger phase-locked spikes in afferent fibers. [ABSTRACT FROM AUTHOR]

Hair cell synapses in the ear and photoreceptor synapses in the eye are the first synapses in the auditory and visual system. These specialized synapses transmit a large amount of sensory information in a fast and efficient manner. Moreover, both small and large signals with widely variable kinetics must be quickly encoded and reliably transmitted to allow an animal to rapidly monitor and react to its environment. Here we briefly review some aspects of these primary synapses, which are characterized by a synaptic ribbon in their active zones of transmitter release. We propose that these synapses are themselves highly specialized for the task at hand. Photoreceptor and bipolar cell ribbon synapses in the retina appear to have versatile properties that permit both tonic and phasic transmitter release. This allows them to transmit changes of both luminance and contrast within a visual field at different ambient light levels. By contrast, hair cell ribbon synapses are specialized for a highly synchronous form of multivesicular release that may be critical for phase locking to low-frequency sound-evoked signals at both low and high sound intensities. The microarchitecture of a hair cell synapse may be such that the opening of a single Ca2+ channel evokes the simultaneous exocytosis of multiple synaptic vesicles. Thus, the differing demands of sensory encoding in the eye and ear generate diverse designs and capabilities for their ribbon synapses. [ABSTRACT FROM AUTHOR]

Aminoglycoside antibiotics (AGAs) are widely used in life-threatening infections, but they accumulate in cochlear hair cells (HCs) and result in hearing loss. Increases in adenosine triphosphate (ATP) concentrations and P2X7 receptor expression were observed after neomycin treatment. Here, we demonstrated that P2X7 receptor, which is a non-selective cation channel that is activated by high ATP concentrations, may participate in the process through which AGAs enter hair cells. Using transgenic knockout mice, we found that P2X7 receptor deficiency protects HCs against neomycin-induced injury in vitro and in vivo. Subsequently, we used fluorescent gentamicin–Fluor 594 to study the uptake of AGAs and found fluorescence labeling in wild-type mice but not in P2rx7−/− mice in vitro. In addition, knocking-out P2rx7 did not significantly alter the HC count and auditory signal transduction, but it did inhibit mitochondria-dependent oxidative stress and apoptosis in the cochlea after neomycin exposure. We thus conclude that the P2X7 receptor may be linked to the entry of AGAs into HCs and is likely to be a therapeutic target for auditory HC protection. Schematic of the role of P2X7 receptor in neomycin-induced HC loss. Under physiological control conditions, P2X7 receptor acts as a channel. ATP and small molecules can pass through it, while large molecules cannot. After neomycin exposure, large amounts of ATP are released from cells and the extracellular concentration of ATP increases rapidly. In addition, more P2X7 receptors are synthesized and appear in the membrane. The high concentrations of ATP cause P2X7 receptor to open as a pore that is large enough for neomycin to enter the HCs, thus damaging the HCs and causing apoptosis. [Display omitted] • AGAs induced cochlear HC damage is associated with changes in eATP concentration and P2X7 receptor activation. • P2X7 receptor is involved to AGAs uptake in HCs. • AGAs-related mitochondria-mediated oxidative stress could be abolished by deleting P2rx7. • P2X7 receptor might be a new target for HC protection from AGAs. [ABSTRACT FROM AUTHOR]