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

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.

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

10.1101/469676 ◽

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

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Developmental Changes in Peripherin-eGFP Expression in Spiral Ganglion Neurons

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.678113 ◽

2021 ◽

Vol 15 ◽

Author(s):

Karen L. Elliott ◽

Jennifer Kersigo ◽

Jeong Han Lee ◽

Israt Jahan ◽

Gabriela Pavlinkova ◽

...

Keyword(s):

Hair Cells ◽

Spiral Ganglion ◽

Outer Hair Cells ◽

Egfp Expression ◽

Spiral Ganglion Neurons ◽

Type Ii ◽

Neuronal Types ◽

Type Ii Cell ◽

Reliable Marker ◽

Ganglion Neurons

The two types of spiral ganglion neurons (SGNs), types I and II, innervate inner hair cells and outer hair cells, respectively, within the mammalian cochlea and send another process back to cochlear nuclei in the hindbrain. Studying these two neuronal types has been made easier with the identification of unique molecular markers. One of these markers, peripherin, was shown using antibodies to be present in all SGNs initially but becomes specific to type II SGNs during maturation. We used mice with fluorescently labeled peripherin (Prph-eGFP) to examine peripherin expression in SGNs during development and in aged mice. Using these mice, we confirm the initial expression of Prph-eGFP in both types I and II neurons and eventual restriction to only type II perikarya shortly after birth. However, while Prph-eGFP is uniquely expressed within type II cell bodies by P8, both types I and II peripheral and central processes continue to express Prph-eGFP for some time before becoming downregulated. Only at P30 was there selective type II Prph-eGFP expression in central but not peripheral processes. By 9 months, only the type II cell bodies and more distal central processes retain Prph-eGFP expression. Our results show that Prph-eGFP is a reliable marker for type II SGN cell bodies beyond P8; however, it is not generally a suitable marker for type II processes, except for central processes beyond P30. How the changes in Prph-eGFP expression relate to subsequent protein expression remains to be explored.

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Differential Expression of Bcl-2 in the Cochlea and Auditory Cortex of a Mouse Model of Age-Related Hearing Loss

Audiology and Neurotology ◽

10.1159/000450937 ◽

2016 ◽

Vol 21 (5) ◽

pp. 326-332 ◽

Cited By ~ 5

Author(s):

Qiuhong Huang ◽

Hao Xiong ◽

Haidi Yang ◽

Yongkang Ou ◽

Zhigang Zhang ◽

...

Keyword(s):

Hearing Loss ◽

Mouse Model ◽

Auditory Cortex ◽

Hair Cells ◽

Spiral Ganglion ◽

Outer Hair Cells ◽

Protective Effects ◽

Age Related ◽

Ganglion Neurons ◽

Age Related Hearing Loss

Bcl-2, the first gene shown to be involved in apoptosis, is a potent regulator of cell survival and known to have protective effects against a variety of age-related diseases. However, the possible relationship between hearing and Bcl-2 expression in the cochlea or auditory cortex of C57BL/6 mice, a mouse model of age-related hearing loss, is still unknown. Using RT-PCR, immunohistochemistry, and Western blot analysis, our results show that Bcl-2 is strongly expressed in the inner hair cells and spiral ganglion neurons of young mice. In addition, moderate Bcl-2 expression is also detected in the outer hair cells and in the neurons of the auditory cortex. A significant reduction of Bcl-2 expression in the cochlea or auditory cortex is also associated with elevated hearing thresholds and hair cell loss during aging. The expression pattern of Bcl-2 in the peripheral and central auditory systems suggests that Bcl-2 may play an important role in auditory function serving as a protective molecule against age-related hearing loss.

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