Abstracts

Rationale: Childhood absence epilepsy is the most common form of epilepsy in the pediatric population. Absence seizures are characterized by pathological spike-wave oscillations arising from the thalamo-cortical circuit. A wide variety of intrinsic currents are known to contribute to neuronal oscillatory behavior, including the T-type calcium current (I_T), the hyperpolarization-activated cation current (I_h) and the persistent sodium current (I_NaP). Ethosuximide, the canonical drug used to treat absence seizures, is known to inhibit I_T. However, Lamotrigine (LTG), which can also be effective in the treatment of absence seizures, does not affect I_T. The mechanism by which LTG exerts its anti-absence effects is still unknown. Outside of the thalamus, LTG has been shown to inhibit both I_hand I_NaP. Here we investigate the effect of lamotrigine on spike-wave discharges in an in vitro model of spike-wave oscillations, and on I_h and I_NaP in the thalamus.Methods: Acute thalamic slices were prepared from P11 P17 Sprague-Dawley rat pups. Absence-like oscillations were electrically evoked via stimulation in the internal capsule and were recorded with tungsten electrodes placed in VB. Apamin and picrotoxin were included in the bath solution to induce epileptiform-like spike-wave discharges. Voltage-clamp recordings of I_h and I_NaP were made using visualized whole-cell recordings in neurons of the VB thalamus. To avoid contamination by superimposed fast sodium currents in recordings of I_NaP, the extracellular concentration of sodium was reduced by 50% with the equimolar substition of choline. LTG was used at 50 M in all experiments.Results: We found that LTG led to early termination of absence-like spike-wave discharges. Specifically, the drug significantly decreased the duration of the oscillation (from 9.7 +/- 0.8 ms to 4.8 +/- .9 ms) and the number of bursts per oscillation (from 28.5 +/- 2.5 bursts to 14.4 +/- 2.3 bursts). We found that LTG had no effect on peak amplitude, tail current, or probability of opening of I_h. However, LTG decreased the peak amplitude of I_NaP to 52 +/- 0.5% of control. Conclusions: Here we demonstrate that LTG significantly inhibits absence-like spike-wave discharges in vitro. There has been some question in the literature as to whether anti-epileptic drugs act on I_NaP in the treatment of absence seizures. We demonstrate for the first time that a block of I_NaP in the thalamus contributes to the mechanism of action of the anti-absence drug LTG.