iem-1460 and Epilepsy

Epileptic activity leads to rapid insertion of calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (CP-AMPARs) into the synapses of cortical and hippocampal glutamatergic neurons, which generally do not express them. The physiological significance of this process is not yet fully understood; however, it is usually assumed to be a pathological process that augments epileptic activity. Using whole-cell patch-clamp recordings in rat entorhinal cortex slices, we demonstrate that the timing of epileptiform discharges, induced by 4-aminopyridine and gabazine, is determined by the shunting effect of Ca

Topics: Adamantane; Animals; Calcium; Computer Simulation; Dizocilpine Maleate; Entorhinal Cortex; Epilepsy; GABA-B Receptor Antagonists; In Vitro Techniques; Male; Membranes; Models, Theoretical; Neurons; Patch-Clamp Techniques; Phosphinic Acids; Propanolamines; Rats, Wistar; Receptors, AMPA; Receptors, GABA-B; Receptors, N-Methyl-D-Aspartate

Many antiseizure drugs (ASDs) act on voltage-dependent sodium channels, and the molecular basis of these effects is well established. In contrast, how ASDs act on the level of neuronal networks is much less understood.. In the present study, we determined the effects of eslicarbazepine (S-Lic) on different types of inhibitory neurons, as well as inhibitory motifs. Experiments were performed in hippocampal slices from both sham-control and chronically epileptic pilocarpine-treated rats.. We found that S-Lic causes an unexpected reduction of feed-forward inhibition in the CA1 region at high concentrations (300 µM), but not at lower concentrations (100 µM). Concurrently, 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 and epileptic animals. In contrast, feedback inhibition was not inhibited by S-Lic. Instead, application of S-Lic, in contrast to previous data for other drugs like carbamazepine (CBZ), resulted in a lasting potentiation of feedback inhibitory post-synaptic currents (IPSCs) only in epileptic and not in sham-control animals, which persisted after washout of S-Lic. We hypothesized that this plasticity of inhibition might rely on anti-Hebbian potentiation of excitatory feedback inputs onto oriens-lacunosum moleculare (OLM) interneurons, which is dependent on Ca. These results suggest that S-Lic affects inhibitory circuits in the CA1 hippocampal region in unexpected ways. In addition, ASD actions may not be sufficiently explained by acute effects on their target channels, rather, it may be necessary to take plasticity of inhibitory circuits into account.

Topics: Adamantane; Animals; Anticonvulsants; CA1 Region, Hippocampal; Calcium; Dibenzazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy; Feedback, Physiological; Hippocampus; Inhibitory Postsynaptic Potentials; Interneurons; Long-Term Potentiation; Muscarinic Agonists; Neural Inhibition; Neuronal Plasticity; Neurons; Pilocarpine; Pyramidal Cells; Rats; Receptors, AMPA