Interferon-α2b Modulates AMPA and Kainate Receptors and Alters Cross Talk of AMPA and NMDA Receptors in the Frog Vestibular Epithelium.

Abstract

Background: Interferons (IFNs) are ototoxic drugs leading to vestibular and auditory disorders. This study investigated the effect of pro-inflammatory cytokine IFN-α2b on the afferent glutamatergic synaptic transmission of the vestibular end organ, focusing on ionotropic glutamate receptors (iGluRs).

Methods: In order to characterize the role of IFN-α2b in the glutamatergic synaptic transmission in vestibular epithelium, we investigated its influence on responses evoked by D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) and kainic acid (kainate). This was carried out using external perfusion of the vestibular apparatus and multiunit recording of afferent firing activity of semicircular canal ampullary nerve fibers. The change in the ratio of the maximum frequency of pulse activity to the preceding background was chosen as a criterion for evaluating the evoked responses of glutamate receptor (GluR) agonists.

Results: Acute perfusion of the vestibular apparatus with IFN-α2b and AMPA did not alter the AMPA-evoked response. However, a significant increase in the response was observed 15 min after cessation of drug application and washing with normal solution (paired-samples t-test p = 0.018; n = 20). IFN-α2b significantly increased the kainate-evoked response during cytokine application (Wilcoxon signed-rank test p = 0.016; n = 11), and further potentiates the response 15 min after rinsing with normal solution, compared to the test value (Wilcoxon signed-rank test p = 0.05; n = 11). IFN had no effect on NMDA-induced responses. AMPA receptors (AMPARs) potentiated by IFN-α2b increase NMDA-evoked responses (Repeated measures analysis of variance [ANOVA RM], p = 0.028; n = 10).

Conclusions: IFN-α2b stimulates AMPARs and kainate receptors (KARs) through various mechanisms but has no direct effect on NMDA receptors (NMDARs). Interferon-activated AMPARs can stimulate NMDARs activity, thereby altering synaptic plasticity of the glutamatergic afferent synapse in vestibular epithelium.