Abstracts

Rationale: Many anti-epileptic drugs (AEDs) act on voltage-dependent sodium channels, and the molecular basis of these effects is well understood. In contrast, how AEDs act on the level of neuronal networks, and how they affect different types of neurons is much less understood. A particularly important question is how AEDs affect inhibitory network motifs in the normal and epileptic brain, because inhibitory neurons are crucial for most types of normal and pathological synchronization. We have previously shown that carbamazepine (CBZ), which is a use-dependent Na+ channel blocker, does not affect inhibitory circuits (Pothmann et al., J Neurosci. 2014; 34:9720). The purpose of the present study was to determine if eslicarbazepine (S-Lic), the active metabolite of the AED eslicarbazepine acetate, shows a similar sparing of inhibition. Methods: We examined S-Lic effects on feed-back and feed-forward inhibition in the hippocampal CA1 region by recording from CA1 pyramidal cells with the patch-clamp technique. Feed-back inhibition was selectively recruited by stimulating CA1 axons in the alveus, while feed-forward inhibition was recruited by stimulating CA3 Schaffer collaterals. In addition, we have recorded from identified interneurons to assess their recruitment into these circuits, and how it is affected by S-Lic. Experiments were performed in hippocampal slices from both sham-control and chronically epileptic pilocarpine-treated animals. Results: We found that feed-back inhibition was largely unaffected by S-Lic even at high concentrations of 300 µM both in sham-control and chronically epileptic animals. Feed-forward inhibition was significantly affected only at 300 µM, but not at 100 µM S-Lic in sham-control and epileptic animals. Consistent with these results, 300 but not 100 µM S-Lic significantly reduced maximal firing rates in putative feed-forward interneurons located in the CA1 stratum radiatum of sham-control animals. In addition, feed forward EPSCs in these interneurons were reduced by 300, but not 100 µM S-Lic. These results suggest that inhibitory circuit function is largely unaffected by 100 µM S-Lic. In contrast, both 100 and 300 µM S-Licsignificantly inhibited repetitive firing of excitatory CA1 pyramidal neurons. Conclusions: Taken together, these results suggest that at concentrations of 100 µM, close to those achieved in patients, S-Licmay spare inhibition, and affect mainly excitatory neurons. It remains to be seen how these effects on specific circuit elements translate to effects of S-Lic on cellular activity patterns during spontaneously developing epileptiform activity. Funding: This study was funded by Bial - Portela & Cª, SA.