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

Document Type : Original Article


1 Department of Audiology, School of Rehabilitation Sciences, Iran University of Medical Sciences. Tehran, Iran

2 Rehabilitation Research Center, Department of Audiology, School of Rehabilitation Sciences, Iran University of Medical Sciences,Tehran, Iran

3 Department of Otorhinolaryngology-Head and Neck Surgery, Imam Khomeini Educational Hospital Complex, Tehran University of Medical Sciences. Tehran, Iran

4 Otorhinolaryngology Research Center, Amir-Alam Educational Complex, Tehran University of Medical Sciences. Tehran, Iran

5 Department of Neurosciences, School of Medicine. Iran University of Medical Sciences. Tehran, Iran

6 Department of Rehabilitation Management, School of Rehabilitation Sciences, Iran University of Medical Sciences. Tehran, Iran


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: 12-guinea pigs as  sham and test groups were exposed to a 4-kHz noise at 104 dB SPL, for 2 hr. Pre-exposure intra-tympanic injection with LY354740 and normal saline 9% 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 1-week post-exposure in both groups. The reduction of wave-I amplitude at 4, 6, and 8 kHz were statistically different between pre- and 1- 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 50 dB SL noise. However, the response detectability increased to 60 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 LY354740 in cochlear synaptopathy.


1. Lu Y. Metabotropic glutamate receptors in auditory processing. Neurosci 2014; 22: 429-445. 
2. Kim KX, Payne Sh, Yang-Hood A, Li SZ, Davis B, Carlquist J, et al. Vesicular glutamatergic transmission in noise-induced loss and repair of cochlear ribbon synapses. J Neurosci 2019; 39: 4434-4447. 
3. Sun Q, Sun JH, Shan XZ, Li XQ. Effect of glutamate on distortion product otoacoustic emission and auditory brainstem response in guinea pigs. Chinese J Otolaryng Head Neck 2005; 40: 435-439. 
4. Liu T, Petrof I, Sherman SM. Modulatory effects of activation of metabotropic glutamate receptors on GABAergic circuits in the mouse cortex. J Neurophysiol 2014; 111: 2287–2297. 
5. Chaki S. Group II metabotropic glutamate receptor agonists as a potential drug for schizophrenia. Eur J Pharmacol 2010; 639: 59- 66.  
6. O’Brien DE, Conn J. Neurobiological insights from mGlu receptor allosteric modulation. Int J Neuropsychoph 2016; 19: 1–10. 
7. Ngomba RT, Luijtelaar GV. Metabotropic glutamate receptors as drug targets for the treatment of absence epilepsy. Curr Opin Pharmacol 2018; 38: 43-50. 
8. Popik P, Kozela E, Pilc A. Selective agonist of group II glutamate metabotropic receptors, LY354740, inhibits tolerance to analgesic effects of morphine in mice. Br J Pharmacol 2000; 130:1425-1431. 
9. Boemer T, Bygrave AM, Chen J, Fernando A, Jackson S, et al. The group II metabotropic glutamate receptor agonist LY354740 and the D2 receptor antagonist haloperidol reduce locomotor hyperactivity but fail to rescue spatial working memory in GluA1 knockout mice. Eur J Neorosci 2017; 45: 912-921. 
10. Lu H, Wang X, Sun W, Hu Y, Gong S. New insights into glutamate ototoxicity in cochlear hair cells and spiral ganglion neurons. Acta Oto Laryngol 2010; 130: 1316–1323. 
11. Liberman MC, Kujawa SG. Cochlear synaptopathy in acquired sensorineural hearing loss: manifestations and mechanisms. Hearing Res 2017; 349: 138-147. 
12. Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov 2005; 4:131-144.
13. Hickman TT, Hashimoto K, Liberman LD, Liberman MC. Cochlear synaptic degeneration and regeneration after noise: effects of age and neuronal subgroup. Front Cell Neurosci 2021; 15:684706. 
14. Ohinata Y, Miller JM, Schacht J. Protection from noise-induced lipid peroxidation and hair cell loss in the cochlea. Brain Res. 2003; 966: 265-273.
15. Yao H, Feng YB, Pang YJ, Yu BX, Liu XP. Inhibitory effect of group II mGluR agonist 2R, 4R-APDC on cell proliferation in dentate gyrus in rats with epileptic seizure. Eur Rev Med Pharmacol Sci. 2015; 19: 2922-2927.
16. Duan M, Agerman K, Ernfors P, Canlon B. Complementary roles of neurotrophin 3 and a N-methyl-D-aspartate antagonist in the protection of noise and aminoglycoside induced ototoxicity. PNAS 2000; 97: 7597-7602. 
17. Chaki S. Group II metabotropic glutamate receptor agonists as a potential drug for schizophrenia. Eur J Pharmacol 2010; 639: 59- 66. 
18. Chandrasekaran K, Muraqundla A, Demarest TG, Choi J, Saqi AR, Najimi N, et al. mGluR2/3 activation of the SIRT1 axis preserves mitochondrial function in diabetic neuropathy. Ann Clin Transl Neurol 2017; 4: 844-858.
19. Bratek E, Zeimbowicz A, Bronisz A, Salinska E. The activation of group II metabotropic glutamate receptors protects neonatal rat brains from oxidative stress injury after hypoxia-ischemia. Plos one 2018; 13: 1-19. 
22. Sadreev II, Burwood GW, Flaherty SM, Kim J, Russell IJ, et al. Drug diffusion along an intact mammalian cochlea. Front Cell Neurosci 2019; 13: 1-11. 
23. Salt AN, Plotke SK. Principles of local drug delivery to the inner ear. Audiol Neurootol 2009; 14: 350-360. 
24. Viberg A. Canlon B. The guide to plotting a cochleogram. Hear Res 2004; 197: 1–10. 
25. Kobel M, Le Prell CG, Liu J, Hawks Jw and Bao J. Noise-induced cochlear synaptopathy: Past findings and future studies. Hear Res 2017; 349:148-154. 
26. Lobarinas E, Spankovich CH, Le Prell CG. Evidence of “hidden hearing loss” following noise exposures that produce robust TTS and ABR wave-I amplitude reductions. Hear Res 2017; 349: 155-163. 
27. Shi L, Chang Y, Li X, Aiken S, Liu L, Wang J. Cochlear synaptopathy and noise-induced hidden hearing loss. Neural Plast 2016; 2016: 1-9. 
28. Kujawa SG, Liberma MC. Adding insult to injury: cochlear nerve degeneration after ‘temporary’ noise-induced hearing loss. J Neurosci 2009; 29, 14077-14085.
29. Lin HW, Furman AC, Kujawa SG, Liberman MC. Primary neural degeneration in the Guinea pig cochlea after reversible noise-induced threshold shift. J Assoc Res Otolaryngol, 2011; 12, 605-616.
30. Valero MD, Burton JA, Hauser SN, Hackett TA, Ramachandran R, Libermn MC. Noise-induced cochlear synaptopathy in rhesus monkeys (Macaca mulatta). Hear Res 2017; 353: 213-223.
31. Paquette AT, Gilels F and White PM. Noise exposure modulates cochlear inner hair cell ribbon volumes, correlating with changes in auditory measures in the FVB/nJ mouse. Sci Rep 2016; 6: 25056. 32. Hickox AE, Larsen E, Heinz MG, Shinobu L, Whitton JP. Translational issues in cochlear synaptopathy. Hear Res 2017; 349: 164-171.
33. Bramhall NF, Konrad-Martin D, McMillan GP and Griest SE. Auditory brainstem response altered in humans with noise exposure despite normal outer hair cell function. Ear Hear 2017; 38: e1–e12. 34. Mehraei X. Hickox AX. Bharadwaj HM. Goldberg H. Verhulst S. Liberman MC, et al. Auditory brainstem response latency in noise as a marker of cochlear synaptopathy. J Neurosci 2016; 36: 3755–3764.
35. Burkard R, Hecox K. The effect of broadband noise on the human brainstem auditory evoked response. I. Rate and intensity effects. J Acoust Soc Am 1983; 74:1204-1213.
36. Song Q, Shen P, Li X, Shi L, Liu L, Wang J, et al. Coding deficits in hidden hearing loss induced by noise: the nature and impacts. Sci Rep 2016; 6: 25200. 
37. Byrnes KR, Loane DJ, Faden AL. Metabotropic glutamate receptors as targets for multipotential treatment of neurological disorders. Neurother 2009; 6: 94-107. 
38. Schoepp DD, Monn JA, Marek GJ, Aghajanian G, Moghadam B. LY354740: A Systemically active mGlu2/mGlu3 receptor agonist. CNS Drug Rev 1999; 5: 1-12.