scholarly journals Inner Hair Cell and Neuron Degeneration Contribute to Hearing Loss in a Dfna2-Like Mouse Model

2018 ◽  
Author(s):  
Camila Carignano ◽  
Esteban Pablo Barila ◽  
Ezequiel Ignacio Rías ◽  
Leonardo Dionisio ◽  
Eugenio Aztiria ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Hair Cells ◽  
Spiral Ganglion ◽  
Outer Hair Cells ◽  
Ganglion Neuron ◽  
Spiral Ganglion Neuron ◽  
Inner Hair Cell ◽  
Neuron Degeneration ◽  
Knock Out

HIGHLIGHTSKCNQ4 knock-out mouse shows hair cells and spiral ganglion neuron degeneration.Inner hair cells and spiral ganglion neuron loss begin 30 weeks later than outer hair cells in Kcnq4-/- mice.Inner hair cell loss kinetic is faster than that of outer hair cells in cochlear basal turn in Kcnq4-/-.Outer hair cells from Kcnq4-/- mice degenerate slower in apical than in basal turn.Kcnq4 knock-out allele expressed in C3H/HeJ strain reproduces the two phases of DFNA2 hearing loss.GRAPHICAL ABSTRACT

scholarly journals MANF supports the inner hair cell synapse and the outer hair cell stereocilia bundle in the cochlea

2021 ◽  
Vol 5 (2) ◽  
pp. e202101068
Author(s):  
Kuu Ikäheimo ◽  
Anni Herranen ◽  
Vilma Iivanainen ◽  
Tuuli Lankinen ◽  
Antti A Aarnisalo ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Er Stress ◽  
Hair Cell ◽  
Hair Cells ◽  
High Frequency ◽  
Outer Hair Cell ◽  
Outer Hair Cells ◽  
Inner Hair Cell ◽  
Age Related ◽  
Er Homeostasis

Failure in the structural maintenance of the hair cell stereocilia bundle and ribbon synapse causes hearing loss. Here, we have studied how ER stress elicits hair cell pathology, using mouse models with inactivation of Manf (mesencephalic astrocyte-derived neurotrophic factor), encoding an ER-homeostasis-promoting protein. From hearing onset, Manf deficiency caused disarray of the outer hair cell stereocilia bundle and reduced cochlear sound amplification capability throughout the tonotopic axis. In high-frequency outer hair cells, the pathology ended in molecular changes in the stereocilia taper region and in strong stereocilia fusion. In high-frequency inner hair cells, Manf deficiency degraded ribbon synapses. The altered phenotype strongly depended on the mouse genetic background. Altogether, the failure in the ER homeostasis maintenance induced early-onset stereociliopathy and synaptopathy and accelerated the effect of genetic causes driving age-related hearing loss. Correspondingly, MANF mutation in a human patient induced severe sensorineural hearing loss from a young age onward. Thus, we present MANF as a novel protein and ER stress as a mechanism that regulate auditory hair cell maintenance in both mice and humans.

scholarly journals Otoferlin Is Required for Proper Synapse Maturation and for Maintenance of Inner and Outer Hair Cells in Mouse Models for DFNB9

2021 ◽  
Vol 15 ◽  
Author(s):  
Ursula Stalmann ◽  
Albert Justin Franke ◽  
Hanan Al-Moyed ◽  
Nicola Strenzke ◽  
Ellen Reisinger
Keyword(s):  
Hair Cells ◽  
Spiral Ganglion ◽  
Outer Hair Cells ◽  
Inner Hair Cell ◽  
Knock Out ◽  
Age Dependent ◽  
Synapse Maturation ◽  
Prelingual Deafness ◽  
Ganglion Neurons ◽  
Synaptic Pruning

Deficiency of otoferlin causes profound prelingual deafness in humans and animal models. Here, we closely analyzed developmental deficits and degenerative mechanisms in Otof knock-out (Otof–/–) mice over the course of 48 weeks. We found otoferlin to be required for proper synapse development in the immature rodent cochlea: In absence of otoferlin, synaptic pruning was delayed, and postsynaptic boutons appeared enlarged at 2 weeks of age. At postnatal day 14 (P14), we found on average ∼15 synapses per inner hair cell (IHC) in Otof–/– cochleae as well as in wild-type controls. Further on, the number of synapses in Otof–/– IHCs was reduced to ∼7 at 8 weeks of age and to ∼6 at 48 weeks of age. In the same period, the number of spiral ganglion neurons (SGNs) declined in Otof–/– animals. Importantly, we found an age-progressive loss of IHCs to an overall number of 75% of wildtype IHCs. The IHC loss more prominently but not exclusively affected the basal aspects of the cochlea. For outer hair cells (OHCs), we observed slightly accelerated age-dependent degeneration from base to apex. This was associated with a progressive decay in DPOAE amplitudes for high frequency stimuli, which could first be observed at the age of 24 weeks in Otof–/– mice. Our data will help to plan and predict the outcome of a gene therapy applied at various ages of DFNB9 patients.

scholarly journals Inhibition of mTOR by Rapamycin Results in Auditory Hair Cell Damage and Decreased Spiral Ganglion Neuron Outgrowth and Neurite FormationIn Vitro

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Katharina Leitmeyer ◽  
Andrea Glutz ◽  
Vesna Radojevic ◽  
Cristian Setz ◽  
Nathan Huerzeler ◽  
...  
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Cell Damage ◽  
Spiral Ganglion ◽  
Ganglion Neuron ◽  
Spiral Ganglion Neuron ◽  
Dependent Manner ◽  
Auditory Hair Cells ◽  
Ganglion Neurons ◽  
Dose Dependent

Rapamycin is an antifungal agent with immunosuppressive properties. Rapamycin inhibits the mammalian target of rapamycin (mTOR) by blocking the mTOR complex 1 (mTORC1). mTOR is an atypical serine/threonine protein kinase, which controls cell growth, cell proliferation, and cell metabolism. However, less is known about the mTOR pathway in the inner ear. First, we evaluated whether or not the two mTOR complexes (mTORC1 and mTORC2, resp.) are present in the mammalian cochlea. Next, tissue explants of 5-day-old rats were treated with increasing concentrations of rapamycin to explore the effects of rapamycin on auditory hair cells and spiral ganglion neurons. Auditory hair cell survival, spiral ganglion neuron number, length of neurites, and neuronal survival were analyzedin vitro. Our data indicates that both mTOR complexes are expressed in the mammalian cochlea. We observed that inhibition of mTOR by rapamycin results in a dose dependent damage of auditory hair cells. Moreover, spiral ganglion neurite number and length of neurites were significantly decreased in all concentrations used compared to control in a dose dependent manner. Our data indicate that the mTOR may play a role in the survival of hair cells and modulates spiral ganglion neuronal outgrowth and neurite formation.

scholarly journals Activity-dependent regulation of prestin expression in mouse outer hair cells

2015 ◽  
Vol 113 (10) ◽  
pp. 3531-3542 ◽  
Author(s):  
Yohan Song ◽  
Anping Xia ◽  
Hee Yoon Lee ◽  
Rosalie Wang ◽  
Anthony J. Ricci ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Hair Cells ◽  
Information Transfer ◽  
Outer Hair Cell ◽  
Endocochlear Potential ◽  
Outer Hair Cells ◽  
Tectorial Membrane ◽  
Inner Hair Cell ◽  
Activity Dependent

Prestin is a membrane protein necessary for outer hair cell (OHC) electromotility and normal hearing. Its regulatory mechanisms are unknown. Several mouse models of hearing loss demonstrate increased prestin, inspiring us to investigate how hearing loss might feedback onto OHCs. To test whether centrally mediated feedback regulates prestin, we developed a novel model of inner hair cell loss. Injection of diphtheria toxin (DT) into adult CBA mice produced significant loss of inner hair cells without affecting OHCs. Thus, DT-injected mice were deaf because they had no afferent auditory input despite OHCs continuing to receive normal auditory mechanical stimulation and having normal function. Patch-clamp experiments demonstrated no change in OHC prestin, indicating that loss of information transfer centrally did not alter prestin expression. To test whether local mechanical feedback regulates prestin, we used TectaC1509G mice, where the tectorial membrane is malformed and only some OHCs are stimulated. OHCs connected to the tectorial membrane had normal prestin levels, whereas OHCs not connected to the tectorial membrane had elevated prestin levels, supporting an activity-dependent model. To test whether the endocochlear potential was necessary for prestin regulation, we studied TectaC1509G mice at different developmental ages. OHCs not connected to the tectorial membrane had lower than normal prestin levels before the onset of the endocochlear potential and higher than normal prestin levels after the onset of the endocochlear potential. Taken together, these data indicate that OHC prestin levels are regulated through local feedback that requires mechanoelectrical transduction currents. This adaptation may serve to compensate for variations in the local mechanical environment.

scholarly journals Disruption of Hars2 in Cochlear Hair Cells Causes Progressive Mitochondrial Dysfunction and Hearing Loss in Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Pengcheng Xu ◽  
Longhao Wang ◽  
Hu Peng ◽  
Huihui Liu ◽  
Hongchao Liu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Mitochondrial Dysfunction ◽  
Hair Cells ◽  
Cell Loss ◽  
Outer Hair Cells ◽  
Hair Cell Loss ◽  
Progressive Hearing Loss ◽  
Cochlear Hair Cells ◽  
Inner Hair Cells

Mutations in a number of genes encoding mitochondrial aminoacyl-tRNA synthetases lead to non-syndromic and/or syndromic sensorineural hearing loss in humans, while their cellular and physiological pathology in cochlea has rarely been investigated in vivo. In this study, we showed that histidyl-tRNA synthetase HARS2, whose deficiency is associated with Perrault syndrome 2 (PRLTS2), is robustly expressed in postnatal mouse cochlea including the outer and inner hair cells. Targeted knockout of Hars2 in mouse hair cells resulted in delayed onset (P30), rapidly progressive hearing loss similar to the PRLTS2 hearing phenotype. Significant hair cell loss was observed starting from P45 following elevated reactive oxygen species (ROS) level and activated mitochondrial apoptotic pathway. Despite of normal ribbon synapse formation, whole-cell patch clamp of the inner hair cells revealed reduced calcium influx and compromised sustained synaptic exocytosis prior to the hair cell loss at P30, consistent with the decreased supra-threshold wave I amplitudes of the auditory brainstem response. Starting from P14, increasing proportion of morphologically abnormal mitochondria was observed by transmission electron microscope, exhibiting swelling, deformation, loss of cristae and emergence of large intrinsic vacuoles that are associated with mitochondrial dysfunction. Though the mitochondrial abnormalities are more prominent in inner hair cells, it is the outer hair cells suffering more severe cell loss. Taken together, our results suggest that conditional knockout of Hars2 in mouse cochlear hair cells leads to accumulating mitochondrial dysfunction and ROS stress, triggers progressive hearing loss highlighted by hair cell synaptopathy and apoptosis, and is differentially perceived by inner and outer hair cells.

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