Metabotropic glutamate receptor: A new possible therapeutic target for cochlear synaptopathy

Objective(s): Cochlear synaptopathy is a common cause of auditory disorders in which glutamate over-activation occurs. Modulating glutamatergic pathways has been proposed to down-regulate post-synaptic excitation.Materials and Methods: ۱۲-guinea pigs as  sham and test groups were exposed to a ۴-kHz noise at ۱۰۴ dB SPL, for ۲ hr. Pre-exposure intra-tympanic injection with LY۳۵۴۷۴۰ and normal saline ۹% was applied in the test and sham groups. The amplitude growth of ABR-wave-I and wave-III latency shift with noise were considered in pre- and post-exposure times. The synapses were observed by transmission electron-microscopy.Results: ABR thresholds recovered ۱-week post-exposure in both groups. The reduction of wave-I amplitude at ۴, ۶, and ۸ kHz were statistically different between pre- and ۱- day post-exposure and recovered mostly in the sham group. The amount of latency shift in masked ABR was different between pre- and all post-exposure, and the response could not be detected at higher than ۵۰ dB SL noise. However, the response detectability increased to ۶۰ dB SL noise, and the significance of differences between pre- and post-exposure persisted only at the high level of noise in the test group. In electron-microscopy of sham samples, the size of the ribbon was larger, spherical with an irregularity, and hollow. The post-synaptic density was thicker and missed its flat orientation.Conclusion: The higher slope of the ABR-wave I amplitude, the more tolerance of noise in masked ABR, concomitant with the histological finding that revealed less synaptic damage, confirmed the therapeutic effect of LY۳۵۴۷۴۰ in cochlear synaptopathy.

Keywords:

Cochlear synaptopathy , Excitotoxicity , Glutamate , Hidden hearing loss , Noise-induced hearing loss