Spiral Ganglion Degeneration and Hearing Loss as a Consequence of Satellite Cell Death in Saposin B-Deficient Mice

Akil, Omar; Sun, Ying; Vijayakumar, Sarath; Zhang, Wujuan; Ku, Tiffany; Lee, Chi-Kyou; Jones, Sherri M.; Grabowski, Gregory A.; Lustig, Lawrence R.

doi:10.1523/jneurosci.3920-13.2015

Cited by 25 publications

(21 citation statements)

References 36 publications

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“…8A) may lead to a differential excitability of cochlear neuronal cells as has been observed for the brain [90,91]. Indeed, dysfunction of satellite cells has been shown to accelerate hearing loss over age and delays ABR wave I responses in high-frequency hearing loss [92] as seen here for Gnai3 KO.…”

Section: Gα I3 Is Essential For Central Auditory Processingsupporting

confidence: 58%

Gαi Proteins are Indispensable for Hearing

Beer‐Hammer

Lee

Mauriac

et al. 2018

Cell Physiol Biochem

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Background/Aims: From invertebrates to mammals, Gα_i proteins act together with their common binding partner Gpsm2 to govern cell polarization and planar organization in virtually any polarized cell. Recently, we demonstrated that Gα_i3-deficiency in pre-hearing murine cochleae pointed to a role of Gα_i3 for asymmetric migration of the kinocilium as well as the orientation and shape of the stereociliary (“hair”) bundle, a requirement for the progression of mature hearing. We found that the lack of Gα_i3 impairs stereociliary elongation and hair bundle shape in high-frequency cochlear regions, linked to elevated hearing thresholds for high-frequency sound. How these morphological defects translate into hearing phenotypes is not clear. Methods: Here, we studied global and conditional Gnai3 and Gnai2 mouse mutants deficient for either one or both Gα_i proteins. Comparative analyses of global versus Foxg1-driven conditional mutants that mainly delete in the inner ear and telencephalon in combination with functional tests were applied to dissect essential and redundant functions of different Gα_i isoforms and to assign specific defects to outer or inner hair cells, the auditory nerve, satellite cells or central auditory neurons. Results: Here we report that lack of Gα_i3 but not of the ubiquitously expressed Gα_i2 elevates hearing threshold, accompanied by impaired hair bundle elongation and shape in high-frequency cochlear regions. During the crucial reprogramming of the immature inner hair cell (IHC) synapse into a functional sensory synapse of the mature IHC deficiency for Gα_i2 or Gα_i3 had no impact. In contrast, double-deficiency for Gα_i2 and Gα_i3 isoforms results in abnormalities along the entire tonotopic axis including profound deafness associated with stereocilia defects. In these mice, postnatal IHC synapse maturation is also impaired. In addition, the analysis of conditional versus global Gα_i3-deficient mice revealed that the amplitude of ABR wave IV was disproportionally elevated in comparison to ABR wave I indicating that Gα_i3 is selectively involved in generation of neural gain during auditory processing. Conclusion: We propose a so far unrecognized complexity of isoform-specific and overlapping Gα_i protein functions particular during final differentiation processes.

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Section: Gα I3 Is Essential For Central Auditory Processingsupporting

confidence: 58%

Gαi Proteins are Indispensable for Hearing

Beer‐Hammer

Lee

Mauriac

et al. 2018

Cell Physiol Biochem

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“…Complete myelination of SGNs and nerve fibers by glial cells is important for proper auditory signal conduction from the peripheral auditory nerve to central auditory processes (Kim et al, 2013 ). Mouse models with abnormal myelination in the inner ear, including Connexin29-deficient mice and Saposin B-deficient mice, have been previously described (Tang et al, 2006 ; Akil et al, 2015 ). In the inner ear, the gap junction protein Connexin29 is highly expressed in myelinating glial cells that ensheath the somas and processes of SGNs.…”

Section: Discussionmentioning

confidence: 99%

“…Immune cells such as macrophages and microglia contribute to nerve refinement in the central nervous system (Paolicelli et al, 2011 ; Schafer et al, 2012 ; Cunningham et al, 2013 ; Miron et al, 2013 ). Macrophages, monocyte-derived phagocytes, are members of the innate immune system and respond to various cytokine/chemokine signals to remove pathogens and apoptotic cells (Tang et al, 2006 ; Guipponi et al, 2007 ; Akil et al, 2015 ). Macrophages have also been detected in the adult cochlea following cochlear insult (Hirose et al, 2005 ; Lang et al, 2006 ; Sato et al, 2010 ; Kaur et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Macrophage-Mediated Glial Cell Elimination in the Postnatal Mouse Cochlea

Brown

Xing

Noble

et al. 2017

Front. Mol. Neurosci.

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Hearing relies on the transmission of auditory information from sensory hair cells (HCs) to the brain through the auditory nerve. This relay of information requires HCs to be innervated by spiral ganglion neurons (SGNs) in an exclusive manner and SGNs to be ensheathed by myelinating and non-myelinating glial cells. In the developing auditory nerve, mistargeted SGN axons are retracted or pruned and excessive cells are cleared in a process referred to as nerve refinement. Whether auditory glial cells are eliminated during auditory nerve refinement is unknown. Using early postnatal mice of either sex, we show that glial cell numbers decrease after the first postnatal week, corresponding temporally with nerve refinement in the developing auditory nerve. Additionally, expression of immune-related genes was upregulated and macrophage numbers increase in a manner coinciding with the reduction of glial cell numbers. Transient depletion of macrophages during early auditory nerve development, using transgenic CD11bDTR/EGFP mice, resulted in the appearance of excessive glial cells. Macrophage depletion caused abnormalities in myelin formation and transient edema of the stria vascularis. Macrophage-depleted mice also showed auditory function impairment that partially recovered in adulthood. These findings demonstrate that macrophages contribute to the regulation of glial cell number during postnatal development of the cochlea and that glial cells play a critical role in hearing onset and auditory nerve maturation.

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“…Sounds are presented and ABRs are recorded in a free field condition as previously described (Akil et al , 2015; Akil et al , 2012; Akil et al , 2006). …”

Section: Methodsmentioning

confidence: 99%

Mouse Auditory Brainstem Response Testing

et al. 2016

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The auditory brainstem response (ABR) test provides information about the inner ear (cochlea) and the central pathways for hearing. The ABR reflects the electrical responses of both the cochlear ganglion neurons and the nuclei of the central auditory pathway to sound stimulation (Zhou et al., 2006; Burkard et al., 2007). The ABR contains 5 identifiable wave forms, labeled as I-V. Wave I represents the summated response from the spiral ganglion and auditory nerve while waves II-V represent responses from the ascending auditory pathway. The ABR is recorded via electrodes placed on the scalp of an anesthetized animal. ABR thresholds refer to the lowest sound pressure level (SPL) that can generate identifiable electrical response waves. This protocol describes the process of measuring the ABR of small rodents (mouse, rat, guinea pig, etc.), including anesthetizing the mouse, placing the electrodes on the scalp, recording click and tone burst stimuli and reading the obtained waveforms for ABR threshold values. As technology continues to evolve, ABR will likely provide more qualitative and quantitative information regarding the function of the auditory nerve and brainstem pathways involved in hearing.

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Spiral Ganglion Degeneration and Hearing Loss as a Consequence of Satellite Cell Death in Saposin B-Deficient Mice

Cited by 25 publications

References 36 publications

Gαi Proteins are Indispensable for Hearing

Gαi Proteins are Indispensable for Hearing

Macrophage-Mediated Glial Cell Elimination in the Postnatal Mouse Cochlea

Mouse Auditory Brainstem Response Testing

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