Injection of pilocarpine, a mucarinic agonist, produces epileptic activity in rats that resembles temporal lobe epilepsy (Turski et al. 1989). Understanding the roles of the kainate family of glutamate receptors in epileptic activity has been hampered by the lack of selective kainate receptor antagonists. We have reported that, in the CA3 region of rat hippocampal slices, antagonists that selectively antagonise the GLUK5 subtype of kainate receptor inhibit high-frequency synaptic transmission (Vignes & Collingridge, 1997) and long-term potentiation (Bortolotto et al. 1999) in the mossy fibre pathway. Here we report the effects of GLUK5 receptor antagonists on epileptiform activity induced by pilocarpine applied acutely to rat hippocampal slices.
Hippocampal slices (400 µm) were obtained from 4- to 6-week-old Wistar rats, killed according to Home Office regulations. Field EPSPs and population spikes were recorded from the cell body layer of the CA3 region in response to low-frequency stimulation of the mossy fibre pathway (Bortolotto et al. 1999).
Perfusion of pilocarpine (15 µM, 20 min) resulted in mossy fibre-evoked and spontaneous epileptiform discharges that persisted for as long as recordings were continued (5 h). Application of a GluK5 receptor antagonist (1.5 µM LY377770 or 10 µM LY382884) from 20 min before until 20 min following the application of pilocarpine had no effect on basal transmission, but greatly reduced or eliminated the generation of epileptiform discharges (n = 4 and 5, respectively). Furthermore, addition of these antagonists reversibly suppressed epileptiform activity that was induced by prior application of pilocarpine (n = 6 and 4, respectively).
We conclude that the GluK5 subtype of kainate receptors may be involved in both the induction and expression of epileptiform activity in this acute model of epilepsy. Therefore, GLUK5 kainate receptors may represent a new target for epilepsy treatment.This work was supported by the Medical Research Council.
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