Inhibition of Excitatory Synaptic Transmission in Hippocampal Neurons by Levetiracetam Involves Zn2+-Dependent GABA Type A Receptor–Mediated Presynaptic Modulation
| Autor: | Kyuya Kogure, Norio Akaike, Masahito Wakita, Naoki Kotani |
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| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 348:246-259 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.113.208751 |
| Popis: | 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 (GABA(A)) 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 GABA(A) 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 GABA(A)-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. |
| Databáze: | OpenAIRE |
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