Modulation of AMPA receptors in cultured cortical neurons induced by the antiepileptic drug levetiracetam

Abstract

Purpose: The present study explores the hypothesis that the antiepileptic mechanism of action of levetiracetam (LEV) is related to effects on alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor channels in mouse cortical neurons in culture.

Methods: The neurons were subjected to the whole-cell configuration of the patch-clamp recording technique and were 8-12 days old in culture.

Results: Kainate elicited concentration-dependent (EC(50)= 80 microM) inward currents in all the patched cells. LEV (5-200 microM) itself did not induce inward or outward currents on all patched neurons, whereas it was effective on the kainate- and AMPA-induced current because it significantly decreased the amplitude of these currents. LEV was also able to significantly decrease the total membrane conductance during kainate perfusion, indicating that its effect was not dependent on the cellular voltage membrane potential. Further evidence that LEV modulated the ionotropic non-NMDA receptors came from the analysis of miniature excitatory postsynaptic currents (mEPSCs). In fact, LEV significantly decreased both the amplitude and the frequency of mEPSCs, as shown by the relative cumulative distributions.

Conclusions: These results reveal that AMPA receptors are modulated by LEV because a significant decrease in the kainate- and AMPA-induced currents and a decrease in amplitude and in frequency of mEPSCs have been observed in cortical neurons in culture. The described effect of LEV on AMPA receptors in cortical neurons is probably due to the etheromeric composition of the receptors and may be considered as a possible new antiepileptic mechanism of action.