Effects of the anticonvulsant retigabine on cultured cortical neurons: changes in electroresponsive properties and synaptic transmission.
The whole-cell patch-clamp technique was used to examine the effects of retigabine, a novel anticonvulsant drug, on the electroresponsive properties of individual neurons as well as on neurotransmission between monosynaptically connected pairs of cultured mouse cortical neurons. Consistent with its known action on potassium channels, retigabine significantly hyperpolarized the resting membrane potentials of the neurons, decreased input resistance, and decreased the number of action potentials generated by direct current injection. In addition, retigabine potentiated inhibitory postsynaptic currents (IPSCs) mediated by activation of gamma-aminobutyric acid(A) (GABA(A)) receptors. IPSC peak amplitude, 90-to-10% decay time, weighted decay time constant, slow decay time constant, and, consequently, the total charge transfer were all significantly enhanced by retigabine in a dose-dependent manner. This effect was limited to IPSCs; retigabine had no significant effect on excitatory postsynaptic currents (EPSCs) mediated by activation of non-N-methyl-D-aspartate ionotropic glutamate receptors. A form of short-term presynaptic plasticity, paired-pulse depression, was not altered by retigabine, suggesting that its effect on IPSCs is primarily postsynaptic. Consistent with the hypothesis that retigabine increases inhibitory neurotransmission via a direct action on the GABA(A) receptor, the peak amplitudes, 90-to-10% decay times, and total charge transfer of spontaneous miniature IPSCs were also significantly increased. Therefore, retigabine potently reduces excitability in neural circuits via a synergistic combination of mechanisms.
Otto
James F
JF
Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112, USA.
Kimball
Matthew M
MM
Wilcox
Karen S
KS
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D004594:Electrophysiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010655:Phenylenediamines / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*
D000927:Anticonvulsants; D002219:Carbamates; D010655:Phenylenediamines; C101866:ezogabine