Abstracts

Cholinergic induced plateau potentials (PPs) are intrinsically generated conductances that can elicit ictal type seizure activity. The aim of this study was to investigate the actions of topiramate on the generation of PPs. The effects of topiramate on the PP were analyzed using whole-cell patch clamp recordings from CA1 pyramidal neurons in rat hippocampal slices. In current clamp, PPs evoked following cholinergic receptor stimulation and action potential bursts were depressed by therapeutically relevant concentrations of topiramate. Conversely, in voltage clamp we discovered that [italic]I[/italic][sub]tail[/sub], a cyclic nucleotide-gated current that underlies PP generation was not depressed. However, significantly longer depolarizing voltage steps were required to elicit [italic]I[/italic][sub]tail[/sub]. This suggested that the calcium entry trigger for evoking PPs was depressed by topiramate and not [italic]I[/italic][sub]tail[/sub] itself. Topiramate had no effect on calcium spikes in control conditions; however topiramate did reduce calcium spikes after cholinergic receptor stimulation. We have found that R-type calcium spikes are enhanced by cholinergic receptor stimulation. Therefore, we isolated R-type calcium spikes, which we found to be depressed by topiramate. We also tested topiramate on recombinant Ca[sub]V[/sub]2.3 calcium channels expressed in tsA-201 cells. Topiramate depressed Ca[sub]V[/sub]2.3 calcium currents by a shift in steady state inactivation. Therefore, we have found that topiramate reduces seizure activity in hippocampal neurons through a novel inhibitory action of R-type calcium channels. (Supported by Canadian Institutes of Health Research, Alberta Heritage Foundation for Medical Research, Canada Research Chair in Neuroscience and R.W. Johnson Pharmaceutical for the gift of topirmate.)