Translational issues in cochlear synaptopathy

Abstract

Understanding the biology of the previously underappreciated sensitivity of cochlear synapses to noise insult, and its clinical consequences, is becoming a mission for a growing number of auditory researchers. In addition, several research groups have become interested in developing therapeutic approaches that can reverse synaptopathy and restore hearing function. One of the major challenges to realizing the potential of synaptopathy rodent models is that current clinical audiometric approaches cannot yet reveal the presence of this subtle cochlear pathology in humans. This has catalyzed efforts, both from basic and clinical perspectives, to investigate novel means for diagnosing synaptopathy and to determine the main functional consequences for auditory perception and hearing abilities. Such means, and a strong concordance between findings in pre-clinical animal models and clinical studies in humans, are important for developing and realizing therapeutics. This paper frames the key outstanding translational questions that need to be addressed to realize this ambitious goal.

Keywords: Cochlear synaptopathy; Hidden hearing loss; Noise-induced hearing loss.

Figure 1. Cochlear synaptopathy in chinchilla

Adult (6–7 mo) male chinchillas were exposed, awake and unrestrained, to an octave-band noise centered at 1 kHz for 2 hrs, at levels ranging from 98–107 dB SPL (animals per group: 98–99 dB: 2, 100–101 dB: 2, 104 dB: 2, 107 dB: 2, unexposed: 7 total, 2 of which were also characterized physiologically). Ears from exposed chinchillas and from unexposed, age- and sex-matched controls were examined by immunolabeling and confocal microscopy to quantitate CtBP2-positive synaptic ribbons as described in Kujawa and Liberman, 2009. Top: Synaptic-ribbon counts were reduced in exposed ears relative to controls, for all exposure levels tested, for mid- and mid-basal cochlear regions. Comparison with ABR threshold shifts in the same ears (bottom) (2 wks post-exposure relative to baseline) demonstrates that cochlear synaptopathy is evident both in cases of TTS and PTS. Key in top panels applies to both. Gray bar indicates noise exposure band. Hickox, Liberman and Heinz, unpublished.

Figure 2. Cochlear synaptopathy in rat

Adult (~250 g) male rats were exposed, anesthetized with ketamine and xylazine, to a two-octave band noise centered at 8 kHz for 1 hr at 119 dB SPL (animals per group: 119 dB: 4, unexposed: 4). Ears from exposed rats and from unexposed, age- and sex-matched controls were examined by immunolabeling and confocal microscopy to quantitate CtBP2-positive synaptic ribbons as described in Kujawa and Liberman, 2009. Top: Synaptic ribbon counts were reduced in exposed ears relative to controls for midand basal cochlear regions. Comparison with DPOAE amplitudes in the exposed ears (bottom) (10 d post-exposure, red; baseline, black) demonstrates that cochlear synaptopathy is evident in both cases of recovered and impaired cochlear sensory cell function. Gray bar indicates noise exposure band. Decibel Therapeutics, unpublished.