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Vol. 61, Issue 4, 921-927, April 2002
Anticonvulsant Drug Development Program, Department of Pharmacology
and Toxicology, University of Utah, Salt Lake City, Utah
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 
-aminobutyric acidA
(GABAA) 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 GABAA 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.
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