Effect of Retigabine on Synaptic Transmission Between Pairs of Cultured Cortical Neurons
Abstract number :
3.164
Submission category :
Year :
2001
Submission ID :
361
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
J.F. Otto, B.S., Pharmacology & Toxicology, University of Utah, Salt Lake City, UT; M.M. Kimball, University of Utah, Salt Lake City, UT; K.S. Wilcox, Ph.D., Pharmacology & Toxicology, University of Utah, Salt Lake City, UT
RATIONALE: The novel anticonvulsant drug retigabine has been found to effectively reduce or block seizure activity in a wide variety of animal models of epilepsy. A primary mechanism of action of retigabine is the enhanced activation of heteromeric potassium channels comprised of the KCNQ2 and KCNQ3 subunits. In addition, retigabine potentiates Cl- currents induced by subsaturating concentrations of exogenously applied GABA. The present set of experiments were conducted in a simple in vitro model system to directly determine the effects of retigabine on excitatory and inhibitory synaptic transmission.
METHODS: Whole-cell patch clamp recordings were obtained from monosynaptically connected pairs of cultured cortical neurons. Action potentials were evoked in the presynaptic neuron and the effects of retigabine on GABA[sub]A[/sub] mediated IPSCs and non-NMDA mediated EPSCs were determined. Miniature IPSCs were recorded in the presence of TTX (500 nM) and CNQX (10 [mu]M).
RESULTS: Retigabine significantly hyperpolarized the membrane potentials of all neurons, and decreased the number of action potentials generated by direct current injection. In addition, retigabine dramatically potentiated IPSCs mediated by activation of GABA[sub]A[/sub] receptors. Peak amplitude, 90-10% decay time, slow decay time constant, and consequently the total charge transfer of IPSCs were all significantly enhanced by retigabine. This effect was limited to IPSCs, as retigabine had no significant effect on EPSCs mediated by activation of non-NMDA ionotropic glutamate receptors. 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[sub]A[/sub] receptor, the peak amplitudes, 90-10% decay times, and total charge transfer of spontaneous miniature IPSCs were also significantly increased.
CONCLUSIONS: Retigabine has both presynaptic and postsynaptic actions that serve to dramatically dampen excitability in neural circuits. These multiple actions likely underlie the potent anticonvulsant profile of this unique compound.
Support: This work was supported by NIH contract N01-NS-4-2311 and an ASPET Summer Fellowship to M.M.K.