Glutamate-aspartate transporter dysfunction enhances aminoglycoside-induced cochlear hair cell death via NMDA receptor activation

Jin Guo; Honglin Mei; Yanping Zhang; Chenhao Che; Luo Guo; Yunzhong Zhang; Huawei Li; Shan Sun

doi:10.1016/j.neuint.2023.105587

Glutamate-aspartate transporter dysfunction enhances aminoglycoside-induced cochlear hair cell death via NMDA receptor activation

Neurochem Int. 2023 Oct:169:105587. doi: 10.1016/j.neuint.2023.105587. Epub 2023 Jul 24.

Authors

Jin Guo¹, Honglin Mei¹, Yanping Zhang¹, Chenhao Che¹, Luo Guo¹, Yunzhong Zhang¹, Huawei Li², Shan Sun³

Affiliations

¹ ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, 200031, China.
² ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China. Electronic address: hwli@shmu.edu.cn.
³ ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, 200031, China. Electronic address: Shansun@fudan.edu.cn.

PMID: 37495172
DOI: 10.1016/j.neuint.2023.105587

Abstract

Glutamate is a crucial neurotransmitter for hearing transduction in the cochlea, but excess glutamate is detrimental to the survival of cochlear sensory cells. Glutamate-aspartate transporter (GLAST) is the major transporter for glutamate removal; however, its role in aminoglycoside-induced hair cell loss is not well studied. In the present study, we first investigated the localization and expression of GLAST over the course of development of the mouse cochlea, and we found that inhibition of GLAST increased hair cell death. However, when the glutamate receptor NMDAR was inhibited by D-AP5, hair cell death was no longer increased by the GLAST inhibitor. Our results indicate that GLAST inhibition aggravates damage to cochlear hair cells, which may occur via NMDAR, and this suggests new clinical strategies for ameliorating the ototoxicity associated with the dysfunction of glutamate metabolism.

Keywords: Aminoglycosides; Glutamate receptor; Glutamate transporter; Hair cell death.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Transport System X-AG / metabolism
Aminoglycosides* / metabolism
Aminoglycosides* / toxicity
Animals
Glutamic Acid / metabolism
Hair Cells, Auditory / metabolism
Mice
Receptors, N-Methyl-D-Aspartate* / metabolism

Substances

Receptors, N-Methyl-D-Aspartate
Aminoglycosides
Amino Acid Transport System X-AG
Glutamic Acid