Synaptopathy in the noise-exposed and aging cochlea: Primary neural degeneration in acquired sensorineural hearing loss

Abstract

The classic view of sensorineural hearing loss (SNHL) is that the "primary" targets are hair cells, and that cochlear-nerve loss is "secondary" to hair cell degeneration. Our recent work in mouse and guinea pig has challenged that view. In noise-induced hearing loss, exposures causing only reversible threshold shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of cochlear-nerve/hair-cell synapses. Similarly, in age-related hearing loss, degeneration of cochlear synapses precedes both hair cell loss and threshold elevation. This primary neural degeneration has remained hidden for three reasons: 1) the spiral ganglion cells, the cochlear neural elements commonly assessed in studies of SNHL, survive for years despite loss of synaptic connection with hair cells, 2) the synaptic terminals of cochlear nerve fibers are unmyelinated and difficult to see in the light microscope, and 3) the degeneration is selective for cochlear-nerve fibers with high thresholds. Although not required for threshold detection in quiet (e.g. threshold audiometry or auditory brainstem response threshold), these high-threshold fibers are critical for hearing in noisy environments. Our research suggests that 1) primary neural degeneration is an important contributor to the perceptual handicap in SNHL, and 2) in cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from spiral ganglion neurons and re-establishment of their peripheral synapses. This article is part of a Special Issue entitled <Auditory Synaptology>.

Figure 1. Immunostaining cochlear epithelial whole mounts to reveal primary cochlear synaptopathy

A: Schematic of the basolateral membrane of an IHC showing three of the 10–20 synapses from ANF terminals that normally contact an IHC in the mouse cochlea. The color scheme for red, green and blue matches that used for the confocal images in Panels C and D. B: Electron micrographs of the active zone between an ANF and an IHC from cat (Liberman, 1980), showing the presynaptic ribbon, its halo of vesicle and the pre- and post-synaptic membrane thickening. In the lower panel of the pair of images, red and green have been superimposed on the micrograph to schematize the immunostained synaptic puncta we count in the confocal. C and D: Maximum projections from z-stacks of the IHC area from the 32 kHz region of a control and a noise-exposed mouse cochlea fixed 1 wk post exposure to the noise band described in Figure 2. Green-filled red arrows point to paired synaptic puncta in both images; red-filled arrow (D only) points to an orphan synaptic ribbon. E: High-power thumbnails of a selection of paired synaptic puncta, arrayed to illustrate the resolution achieved in the confocal and the trend that synapses with larger post-synaptic receptor patches (GluA2, green) tend to be paired with smaller pre-synaptic ribbons (CtBP2, red), and vice versa (Liberman et al., 2011).

Figure 2. Permanent cochlear synaptopathy after exposure causing largely reversible threshold shift

A: Synaptic puncta were counted in the IHC area from 8 cochlear locations in control ears (n=16) and noise-exposed ears (n=6 at each post-exposure time), exposed at 8 wks of age and assessed either 24 hrs or 1 wk after exposure to an 8–16 kHz octave band noise at 98 dB for 2 hrs. B: Thresholds in the noise-exposed ears, as measured by DPOAEs, were elevated at 24 hrs post exposure by 25–30 dB in the basal half of the cochlea, but had completely recovered at all but the highest test frequency by 1 wk post exposure. For further details on methodology, see prior studies from our laboratories (Kujawa et al., 2009; Liberman et al., 2015; Liberman et al., 2014).