Elsevier

Hearing Research

Volume 221, Issues 1–2, November 2006, Pages 104-118
Hearing Research

Research paper
Synaptic alterations at inner hair cells precede spiral ganglion cell loss in aging C57BL/6J mice

https://doi.org/10.1016/j.heares.2006.07.014Get rights and content

Abstract

Hearing deficits have often been associated with loss of or damage to receptor hair cells and/or degeneration of spiral ganglion cells. There are, however, some physiological abnormalities that are not reliably attributed to loss of these cells. The afferent synapse between radial fibers of spiral ganglion neurons and inner hair cells (IHCs) emerges as another site that could be involved in transmission abnormalities. We tested the hypothesis that the structure of these afferent terminals would differ between young animals and older animals with significant hearing loss. Afferent endings and their synapses were examined by transmission electron microscopy at approximately 45% distance from the basal end of the cochlea in 2–3 month-old and 8–12 month-old C57BL/6J mice. The number of terminals in older animals was reduced by half compared to younger animals. In contrast, there was no difference in the density of SGCs between the age groups. Older animals featured enlarged terminals and mitochondria and enlarged postsynaptic densities and presynaptic bodies. These morphological changes may be a combination of pathologic, adaptive and compensatory responses to sensory dysfunction. Improved knowledge of these processes is necessary to understand the role of afferent connectivity in dysfunction of the aging cochlea.

Introduction

Changes at the interface between receptor cells and afferent endings represent a poorly understood stage in the progression of hearing dysfunction associated with presbycusis. It is now well established that loss of radial fibers can exceed the loss of spiral ganglion cell bodies in human cases of presbycusis (Chen et al., 2006, Nadol, 1979, Pauler et al., 1986, Spoendlin and Schrott, 1988, Spoendlin and Schrott, 1990). A distal-to-proximal gradient of radial fiber loss has also been observed in C57BL/6J mice (White et al., 2000), a laboratory animal model that exhibits patterns of hearing loss and cochlear degeneration comparable to human presbycusis (Francis et al., 2003, Henry and Chole, 1980, Hequembourg and Liberman, 2001, Li and Borg, 1991). Alterations in sensory–neural synaptic structure that precede or follow denervation may hold the key to understanding the mechanisms of afferent cochlear pathology. Since auditory information is conveyed to the brain by the pattern of action potentials in the auditory nerve, rearrangement and/or degradation of synaptic components at this location will affect the encoding process. Corruption of transmission through the IHC-afferent fiber synapse would disturb the fidelity of spike timing represented within the auditory nerve and change the very signals upon which speech understanding ultimately depends.

Synaptic alterations have been documented in the aging central nervous system where a reduction in cortical synaptic density and increase in synaptic size are associated with cognitive decline in humans (Bertoni-Freddari and Fattoretti, 1989) and senescence in laboratory animals (Bertoni-Freddari et al., 1996). Changes in the proportion of low- and high-spontaneous rate fibers were observed in cats with noise-induced hearing loss (Liberman and Dodds, 1984), congenital hearing loss (Ryugo et al., 1998), and gerbils with age-induced hearing loss (Schmiedt et al., 1996). Because specific ultrastructural features are associated with discharge properties of auditory nerve fibers (Liberman and Dodds, 1984), they may exhibit alterations that accompany specific physiological changes.

On the basis of these considerations, we conducted a morphometric study of the innervation of IHCs in the C57BL/6J mouse at two ages with known differences in hearing sensitivity. We tested the hypothesis that the structure of afferent terminals and their synapses with IHCs is different between young adult and older animals, and argue that the observed changes in synaptic organization represent part of the substrate underlying age-related hearing loss.

Section snippets

Animals

Female C57BL/6J mice with documented dates of birth were obtained from Jackson Laboratories. Three mice were studied at 2–3 months of age (the younger group) and three were studied at 8–12 months of age (the older group). No outer or middle ear pathology was encountered in any of the animals studied. All procedures were conducted in accordance with an animal protocol approved by the Animal Care and Use Committee at the Johns Hopkins University School of Medicine.

Hearing assessment

Hearing thresholds were measured

Results

Diminished hearing sensitivity in older animals was accompanied by partial OHC loss, whereas IHCs and SGCs were preserved. Available auditory brainstem response (ABR) measurements in two younger mice suggest normal to mildly reduced sensitivity in this age group and a significant elevation of thresholds in older animals (Table 1, Fig. 1). Light microscopic examination of the cochlear region that was subsequently studied with an electron microscope revealed comparable densities of IHCs (younger

Discussion

We describe age-related structural changes at the synaptic interface between afferent nerve endings and IHCs in C57BL/6J mouse, an animal model of presbycusis. The number of radial fiber afferent synapses is reduced in excess of spiral ganglion cell loss and precedes IHC loss. Structural changes below the resolution of the light microscope are likely to accompany even earlier stages of hearing loss than were examined here. A report of lower distal and higher proximal fiber densities in the

Acknowledgements

This research was supported by NIH/NIDCD Grants DC00143, DC05909, DC05211, DC00232, and by Grants provided by the American Hearing Research Foundation, Deafness Research Foundation and National Organization for Hearing Research. We thank Elliot Hogg and Zeyar Min for their technical assistance.

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