Levetiracetam inhibits glutamate transmission through presynaptic P/Q-type calcium channels on the granule cells of the dentate gyrus

Background and purpose: Levetiracetam is an effective anti-epileptic drug in the treatment of partial and generalized seizure. The purpose of the present study was to investigate whether levetiracetam regulates AMPA and NMDA receptor-mediated excitatory synaptic transmission and to determine its site of action in the dentate gyrus (DG), the area of the hippocampus that regulates seizure activities. Experimental approach: Whole-cell patch-clamp method was used to record the AMPA and NMDA receptor-mediated excitatory postsynaptic currents (EPSCAMPA and EPSCNMDA) in the presence of specific antagonists, from the granule cells in the DG in brain slice preparations from young Wistar rats (60-120 g). Key results: Levetiracetam (100 mu M) inhibited both evoked EPSCAMPA and EPSCNMDA to an equal extent (80%), altered the paired-pulse ratio (from 1.39 to 1.25), decreased the frequency of asynchronous EPSC and prolonged the inter-event interval of miniature EPSCAMPA (from 2.7 to 4.6 s) without changing the amplitude, suggesting a presynaptic action of levetiracetam. The inhibitory effect of levetiracetam on evoked EPSCAMPA was blocked by omega-agatoxin TK (100 nM), a selective P/Q-type voltage-dependent calcium channel blocker, but not by nimodipine (10 mu M) or omega-conotoxin (400 nM). Conclusions and implications: These results suggest that levetiracetam modulated the presynaptic P/Q-type voltage-dependent calcium channel to reduce glutamate release and inhibited the amplitude of EPSC in DG. This effect is most likely to contribute to the anti-epileptic action of levetiracetam in patients.