TY - JOUR T1 - Inhibition of Excitatory Synaptic Transmission in Hippocampal Neurons by Levetiracetam Involves Zn<sup>2+</sup>-Dependent GABA Type A Receptor–Mediated Presynaptic Modulation JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 246 LP - 259 DO - 10.1124/jpet.113.208751 VL - 348 IS - 2 AU - Masahito Wakita AU - Naoki Kotani AU - Kyuya Kogure AU - Norio Akaike Y1 - 2014/02/01 UR - http://jpet.aspetjournals.org/content/348/2/246.abstract N2 - Levetiracetam (LEV) is an antiepileptic drug with a unique but as yet not fully resolved mechanism of action. Therefore, by use of a simplified rat-isolated nerve-bouton preparation, we have investigated how LEV modulates glutamatergic transmission from mossy fiber terminals to hippocampal CA3 neurons. Action potential–evoked excitatory postsynaptic currents (eEPSCs) were recorded using a conventional whole-cell patch-clamp recording configuration in voltage-clamp mode. The antiepileptic drug phenytoin decreased glutamatergic eEPSCs in a concentration-dependent fashion by inhibiting voltage-dependent Na+ and Ca2+ channel currents. In contrast, LEV had no effect on eEPSCs or voltage-dependent Na+ or Ca2+ channel currents. Activation of presynaptic GABA type A (GABAA) receptors by muscimol induced presynaptic inhibition of eEPSCs, resulting from depolarization block. Low concentrations of Zn2+, which had no effect on eEPSCs, voltage-dependent Na+ or Ca2+ channel currents, or glutamate receptor–mediated whole cell currents, reduced the muscimol-induced presynaptic inhibition. LEV applied in the continuous presence of 1 µM muscimol and 1 µM Zn2+ reversed this Zn2+ modulation on eEPSCs. The antagonizing effect of LEV on Zn2+-induced presynaptic GABAA receptor inhibition was also observed with the Zn2+ chelators Ca-EDTA and RhodZin-3. Our results clearly show that LEV removes the Zn2+-induced suppression of GABAA-mediated presynaptic inhibition, resulting in a presynaptic decrease in glutamate-mediated excitatory transmission. Our results provide a novel mechanism by which LEV may inhibit neuronal activity. ER -