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

Autor:	Stalmann U; Auditory Systems Physiology Group, Department of Otolaryngology and Institute for Auditory Neuroscience, SFB 889 project A06, University Medical Center Göttingen, Göttingen, Germany., Franke AJ; Auditory Systems Physiology Group, Department of Otolaryngology and Institute for Auditory Neuroscience, SFB 889 project A06, University Medical Center Göttingen, Göttingen, Germany., Al-Moyed H; Molecular Biology of Cochlear Neurotransmission Group, Department of Otolaryngology, University Medical Center Göttingen, Göttingen, Germany., Strenzke N; Auditory Systems Physiology Group, Department of Otolaryngology and Institute for Auditory Neuroscience, SFB 889 project A06, University Medical Center Göttingen, Göttingen, Germany., Reisinger E; Molecular Biology of Cochlear Neurotransmission Group, Department of Otolaryngology, University Medical Center Göttingen, Göttingen, Germany.; Gene Therapy for Hearing Impairment Group, Department of Otolaryngology, Head and Neck Surgery, University of Tübingen Medical Center, Tübingen, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in cellular neuroscience [Front Cell Neurosci] 2021 Jul 14; Vol. 15, pp. 677543. Date of Electronic Publication: 2021 Jul 14 (Print Publication: 2021).
DOI:	10.3389/fncel.2021.677543
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Stalmann, Franke, Al-Moyed, Strenzke and Reisinger.)
Databáze:	MEDLINE
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