Inhibition of Excitatory Synaptic Transmission in Hippocampal Neurons by Levetiracetam Involves Zn²⁺-Dependent GABA Type A Receptor–Mediated Presynaptic Modulation

Abstract

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 1 and Ca 21 channel currents. In contrast, LEV had no effect on eEPSCs or voltage-dependent Na

Modifications of excitatory and inhibitory transmission in rat hippocampal pyramidal neurons by acute lithium treatment

“…These concentrations correspond to ED 20-30 values of their concentration-response curves. At these concentrations cells give consistent responses with little desensitization (Matsuura et al, 2011;Yamamoto et al, 2011;Iwata et al, 2013;Wakita et al, 2014). The effects of Li + on the responses were quantified by normalizing the peak current amplitudes in the control condition.…”

GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system

“…In contrast to those on axoaxonic synapses, most presynaptic GABA A Rs located on distal axons and terminals are hardly detectable by immunohistochemistry. They nevertheless play a key role in the control of axon potential transmission, neuronal synchronisation, regulation of transmitter release, and mediation of presynaptic afferent depolarisation (Trigo et al, 2008;Long et al, 2009;Ruiz et al, 2010;Wakita et al, 2013). Although their subunit composition is unknown, it might be inferred from the repertoire of subunit mRNAs expressed by the cell of origin of these axons.…”

Mechanisms of Levetiracetam in the Control of Status Epilepticus and Epilepsy

“…Levetiracetam has been shown to affect GABA turnover in the striatum and decrease levels of the amino acid taurine, a low affinity agonist for GABA A receptors, in the hippocampus with no effect in other amino acids (38). In addition, LEV removed the Zn 2+ -induced suppression of GABA A -mediated presynaptic inhibition, resulting in a presynaptic decrease in glutamate mediated excitatory transmission (39). Other reports have also suggested that the mechanisms of the anti-epileptic and neuroprotective actions of LEV seem to be mediated, at least in part, through the combination of inhibitory effects on depolarization-induced and Ca 2+ -induced Ca 2+ release-associated neurotransmitter releases (40).…”