Selective Antagonism of GluR5 Kainate-Receptor-Mediated Synaptic Currents by Topiramate in Rat Basolateral Amygdala Neurons

摘要

Topiramate is a widely used antiepileptic agent whose mechanism of action is poorly understood. The drug has been reported to interact with various ion channel types, including AMPA/kainate receptors. In whole-cell voltage-clamp recordings from principal neurons of the rat basolateral amygdala, topiramate at low concentrations (IC50, ∼0.5 μm) selectively inhibited pharmacologically isolated excitatory synaptic currents mediated by kainate receptors containing the GluR5 subunit. Topiramate also partially depressed predominantly AMPA-receptor-mediated EPSCs, but with lower efficacy. Topiramate did not alter the degree of facilitation in paired-pulse experiments, and it reduced the amplitude of miniature EPSCs without affecting their frequency, demonstrating that the block of synaptic responses occurs postsynaptically. Inhibition of GluR5 kainate receptors could represent a key mechanism underlying the anticonvulsant activity of topiramate. Moreover, these results support the concept that GluR5 kainate receptors represent a novel target for antiepileptic drug development.