Development of cochlear neuropathy in adenosine receptor knockout mice

Abstract

Noise-induced-hearing loss (NIHL) is considered to be a significant cause of sensorineural hearing loss, accounting for approximately 16% of hearing impairment worldwide. NIHL is mainly associated with cochlear injury and particularly degeneration of sensory hair cells and spiral ganglion neurons. Rehabilitation of hearing loss via prosthetic devices (hearing aids and cochlear implants) is the only current management strategies for NIHL and other forms of sensorineural hearing loss (SNHL). Hence, it is essential to develop pharmacological and molecular therapies that can ameliorate or repair injury to the delicate structures of the inner ear and thus reduce the impact of hearing loss. Our research group has identified the adenosine signalling system as one of the most promising targets for the therapeutic management of SNHL. Here, we investigate the broader role of A1 and A2A adenosine receptors in the development of cochlear injury with acoustic trauma using genetically modified mice that lack genes for the two main types of adenosine receptors found in the inner ear (A1 and A2A receptors). These mice were exposed to a 8-16 kHz octave band noise at 100 dB sound pressure level (SPL) for a period of 2 hours to induce cochlear injury and permanent hearing loss. Auditory thresholds and suprathreshold responses were assessed using auditory brainstem responses (ABR) before and two weeks post-exposure and the loss of afferent synapses and spiral ganglion neurons were assessed histologically. Our study demonstrates a pre-exposure high frequency hearing loss in A1RKO mice similar to age related hearing loss in ageing C57BL/6 wildtype mice. In addition, suprathreshold responses (ABR wave II amplitudes) were severely reduced in A1RKO mice, reflecting poor functioning of auditory nerve fibres prior to noise exposure. This hearing loss was further aggravated by noise exposure. A1RKOs also experienced a significantly greater loss of SGNs than wildtype mice of the same background. In contrast, the genetic deletion of the A2A receptor resulted in a higher number of functional synapses per IHC and minimal loss of SGNs. Our results suggest that the A1 receptor deficiency likely results in increased susceptibility to oxidative stress and glutamate excitotoxicity in the noise-exposed cochlea. In contrast, the A2A receptor deficiency appears to increase cochlear resistance to acoustic trauma. Distinct auditory phenotypes of A1RKO and A2ARKO mice suggest that the manipulation of the adenosine signalling system holds significant promise in the therapeutic management of NIHL and related pathologies. Our study thus provides a framework for further investigations of the otoprotective role of adenosine signalling in the inner ear, based on stimulation of A1 receptors and inhibition of A2A receptors.