Topiramate inhibits the initiation of plateau potentials in CA1 neurons by depressing R-type calcium channels

Purpose: Cholinergic-dependent 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 (TPM) on the generation of PPs. Methods: We used whole-cell patch-clamp recordings from CA1 pyramidal neurons in rat hippocampal slices to examine the effects of TPM on the PPs. Results: In current-clamp mode, action potentials evoked PPs after cholinergic receptor stimulation. Therapeutically relevant concentrations of TPM (50 mu M) depressed the PPs evoked by action potentials. Surprisingly, in voltage-clamp mode, we discovered that the cyclic nucleotide-gated (CNG) current that underlies PP generation (denoted as I-tail) was not depressed. However, significantly longer depolarizing voltage steps were required to elicit I-tail. This suggested that the calcium entry trigger for evoking PPs was depressed by TPM and not I-tail itself. TPM had no effect on calcium spikes in control conditions; however, TPM did reduce calcium spikes after cholinergic-receptor stimulation. We recently found that R-type calcium spikes are enhanced by cholinergic-receptor stimulation. Therefore we isolated R-type calcium spikes with a cocktail containing tetrodotoxin, omega-conotoxin MVIIC, omega-conotoxin-GVIA, omega-agatoxin IVA, and nifedipine. R-type calcium spikes were significantly depressed by TPM. We also examined the effects of TPM on recombinant Ca(V)2.3 calcium channels expressed in tsA-201 cells. TPM depressed currents mediated by Ca(V)2.3 subunits by a hyperpolarizing shift in steady-state inactivation. Conclusions: We have found that TPM reduces ictal-like activity in CA1 hippocampal neurons through a novel inhibitory action of R-type calcium channels.