AMPA-preferring glutamate receptors in cochlear physiology of adult guinea-pig.
1. The present study was designed to determine which glutamate (Glu) receptors are involved in excitatory neurotransmission at the first auditory synapse between the inner hair cells and the spiral ganglion neurons. 2. The Glu receptors present at the membrane level were investigated on isolated spiral ganglion neuron somata from guinea-pigs by whole-cell voltage-clamp measurements. Glu and AMPA induced a fast onset inward current that was rapidly desensitized, while kainate induced only a non-desensitizing, steady-state current. NMDA induced no detectable current. 3. To further discriminate between the AMPA and kainate receptors present, we used the receptor-specific desensitization blockers, cyclothiazide and concanavalin A. While no effect was observed with concanavalin A, cyclothiazide greatly enhanced the Glu-, AMPA- and kainate-induced steady-state currents and potentiated Glu-induced membrane depolarization. 4. To extrapolate the results obtained from the somata to the events occurring in situ at the dendrites, the effects of these drugs were evaluated in vivo. Cyclothiazide reversibly increased spontaneous activity of single auditory nerve fibres, while concanavalin A had no effect, suggesting that the functional Glu receptors on the somata may be the same as those at the dendrites. 5. The combination of a moderate-level sound together with cyclothiazide increased and subsequently abolished the spontaneous and the sound-evoked activity of the auditory nerve fibres. Histological examination revealed destruction of the dendrites, suggesting that cyclothiazide potentiates sound-induced Glu excitotoxicity via AMPA receptors. 6. Our results reveal that fast synaptic transmission in the cochlea is mainly mediated by desensitizing AMPA receptors.
Department of Otorhinolaryngology, Louisiana State University Medical Center, 2020 Gravier Street, Suite A, New Orleans, LA 70112, USA.
J
J
Ruel
C
C
Chen
R
R
Pujol
R P
RP
Bobbin
J L
JL
Puel
D000818:Animals; D001581:Benzothiadiazines / Q000494:pharmacology; D003051:Cochlea / Q000502:physiology*; D003208:Concanavalin A / Q000494:pharmacology; D003712:Dendrites / Q000187:drug effects / Q000502:physiology; D004558:Electric Stimulation; D004594:Electrophysiology; D006168:Guinea Pigs; D006199:Hair Cells, Auditory, Inner / Q000502:physiology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000502:physiology; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D009925:Organ of Corti / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000502:physiology*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000502:physiology; D013136:Spiral Ganglion / Q000166:cytology / Q000502:physiology; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D000159:Vestibulocochlear Nerve / Q000187:drug effects / Q000502:physiology
D001581:Benzothiadiazines; D003208:Concanavalin A; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C004639:cyclothiazide