T-current related effects of antiepileptic drugs and a Ca 2+ channel antagonist on thalamic relay and local circuit interneurons in a rat model of absence epilepsy

Abstract

Channel blocking, anti-oscillatory, and anti-epileptic effects of clinically used anti-absence substances (ethosuximide, valproate) and the T-type Ca 2+ current ( I T) blocker mibefradil were tested by analyzing membrane currents in acutely isolated local circuit interneurons and thalamocortical relay (TC) neurons, slow intrathalamic oscillations in brain slices, and spike and wave discharges (SWDs) occurring in vivo in Wistar Albino Glaxo rats from Rijswijk (WAG/Rij). Substance effects in vitro were compared between WAG/Rij and a non-epileptic control strain, the ACI rats. Ethosuximide (ETX) and valproate were found to block I T in acutely isolated thalamic neurons. Block of I T by therapeutically relevant ETX concentrations (0.25–0.75 mM) was stronger in WAG/Rij, although the maximal effect at saturating concentrations (≥10 mM) was stronger in ACI. Ethosuximide delayed the onset of the low threshold Ca 2+ spike (LTS) of neurons recorded in slice preparations. Mibefradil (≥2 μM) completely blocked I T and the LTS, dampened evoked thalamic oscillations, and attenuated SWDs in vivo. Computational modeling demonstrated that the complete effect of ETX can be replicated by a sole reduction of I T. However, the necessary degree of I T reduction was not induced by therapeutically relevant ETX concentrations. A combined reduction of I T, the persistent sodium current, and the Ca 2+ activated K + current resulted in an LTS alteration resembling the experimental observations. In summary, these results support the hypothesis of I T reduction as part of the mechanism of action of anti-absence drugs and demonstrate the ability of a specific I T antagonist to attenuate rhythmic burst firing and SWDs.