Functional roles of high-affinity glutamate transporters in cochlear afferent synaptic transmission in the mouse.
In the cochlea, afferent transmission between inner hair cells and auditory neurons is mediated by glutamate receptors. Glutamate transporters located near the synapse and in spiral ganglion neurons are thought to maintain low synaptic levels of glutamate. We analyzed three glutamate transporter blockers for their ability to alter the effects of glutamate, exogenously applied to the synapse via perfusion of the scala tympani of the mouse, and compared that action to their ability to alter the effects of intense acoustic stimulation. Threo-beta-benzyloxyaspartate (TBOA) is a broad-spectrum glutamate transporter antagonist, affecting all three transporters [glutamate/aspartate transporter (GLAST), glutamate transporter-1 (GLT1), and excitatory amino acid carrier 1 (EAAC1)]. l-serine-O-sulfate (SOS) blocks both GLAST and EAAC1 without effect on GLT1. Dihydrokainate (DHK) is selective for GLT1. Infusion of glutamate (10 microM for 220 min), TBOA (200 microM for 220 min), or SOS (100 microM for 180 min) alone did not alter auditory neural thresholds. When infused together with glutamate, TBOA and SOS produced significant neural threshold shifts, leaving otoacoustic emissions intact. In addition, both TBOA and SOS exacerbated noise-induced hearing loss by producing larger neural threshold shifts and delaying recovery. DHK did not alter glutamate- or noise-induced hearing loss. The evidence points to a major role for GLAST, both in protecting the synapse from exposure to excess extracellular glutamate and in attenuating hearing loss due to acoustic overstimulation.
Chen
Zhiqiang
Z
Eaton Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston MA 02114, USA.
Kujawa
Sharon G
SG
Sewell
William F
WF
D000161:Acoustic Stimulation; D000818:Animals; D001309:Auditory Threshold / Q000187:drug effects / Q000502:physiology; D003051:Cochlea / Q000187:drug effects / Q000502:physiology*; D003056:Cochlear Nerve / Q000187:drug effects / Q000502:physiology; D027341:Excitatory Amino Acid Transporter 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050580:Excitatory Amino Acid Transporter 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects / Q000502:physiology; D006309:Hearing / Q000187:drug effects / Q000502:physiology*; D006317:Hearing Loss, Noise-Induced / Q000503:physiopathology; D051379:Mice; D008808:Mice, Inbred CBA; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D012533:Scala Tympani / Q000187:drug effects / Q000502:physiology; D013136:Spiral Ganglion / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D027341:Excitatory Amino Acid Transporter 1; D050580:Excitatory Amino Acid Transporter 3; D051272:Glucose Transporter Type 1; C493399:Slc1a1 protein, mouse; C493393:Slc1a3 protein, mouse; C495678:Slc2a1 protein, mouse; D018698:Glutamic Acid