Topiramate inhibits the initiation of plateau potentials in CA1 neurons by depressing R-type calcium channels.
OBJECTIVE
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 microM) 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.
Kuzmiski
Joseph Brent
JB
Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.
Barr
Wendy
W
Zamponi
Gerald W
GW
MacVicar
Brian A
BA
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020908:Calcium Channels, R-Type / Q000187:drug effects* / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology; D012640:Seizures / Q000503:physiopathology / Q000517:prevention & control; D000077236:Topiramate; D014162:Transfection
D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D020908:Calcium Channels, R-Type; D011976:Receptors, Muscarinic; D000077236:Topiramate; D005632:Fructose; D002217:Carbachol