Virally mediated enhancement of efferent inhibition reduces acoustic trauma in wild-type murine cochleas

Abstract

Noise-induced hearing loss (NIHL) poses an emerging global health problem with only ear protection or sound avoidance as preventive strategies. The cochlea receives some protection from medial olivocochlear efferent neurons, providing a potential target for therapeutic enhancement. Cholinergic efferents release acetylcholine (ACh) to hyperpolarize and shunt the outer hair cells (OHCs), reducing sound-evoked activation. The (α9)2(α10)3 nicotinic ACh receptor (nAChR) on the OHCs mediates this effect. Transgenic knockin mice with a gain-of-function nAChR (α9L9′T) suffer less NIHL. α9 knockout mice are more vulnerable to NIHL but can be rescued by viral transduction of the α9L9′T subunit. In this study, an HA-tagged gain-of-function α9 isoform was expressed in wild-type mice to reduce NIHL. Synaptic integration of the virally expressed nAChR subunit was confirmed by HA immunopuncta localized to the postsynaptic membrane of OHCs. After noise exposure, AAV2.7m8-CAG-α9L9′T-HA (α9L9′T-HA)-injected mice had less hearing loss (auditory brainstem response [ABR] thresholds and threshold shifts) than did control mice. ABRs of α9L9′T-HA-injected mice also had larger wave-1 amplitudes and better recovery of wave-1 amplitudes post noise exposure. Thus, virally expressed α9L9′T combines effectively with native α9 and α10 subunits to mitigate NIHL in wild-type cochleas.

Keywords

• gene therapy
• adeno-associated virus
• noise-induced hearing loss
• cochlear efferents
• outer hair cell
• olivocochlear system