Glutamate receptor involvement in dentate granule cell epileptiform activity evoked by mossy fiber stimulation.

In many persons with temporal lobe epilepsy, dentate granule cells form an interconnected synaptic network. This recurrent mossy fiber circuit mediates reverberating excitation that may facilitate seizure propagation by synchronizing granule cell discharge. The involvement of specific glutamate receptors in granule cell epileptiform activity evoked by stimulating the mossy fibers was investigated with use of rat hippocampal slices superfused with bicuculline, with or without increasing [K+](o) to 6 mM. The occurrence of short-latency mossy fiber-evoked granule cell epileptiform activity in slices from pilocarpine-treated rats correlated with the presence and extent of recurrent mossy fiber growth. Blockade of AMPA receptors nearly abolished the orthodromic component of the response; subsequent antagonism of kainate receptors as well appeared to have no further action. Antagonism of NMDA receptors reduced the duration of epileptiform discharge, but increased the amplitude of population spikes within the evoked burst. Thus AMPA and NMDA, but perhaps not kainate, receptors play an important role in this type of epileptiform activity. Activation of type II metabotropic glutamate receptors, which inhibits the release of glutamate from mossy fiber boutons, reduced the magnitude of epileptiform discharge. This action was reversed by a partial agonist of these receptors. However, neither an agonist nor an antagonist of type III metabotropic glutamate receptors significantly altered the response. Considering the importance of synchronous granule cell discharge for seizure propagation from the entorhinal cortex to the hippocampus, agonists of type II metabotropic glutamate receptors may be useful in suppressing such discharge both experimentally and clinically.

Duke Scholars

Author J. Victor Nadler Pharmacology & Cancer Biology