title: Function of inhibitory micronetworks is spared by Na+ channel-acting anticonvulsant drugs.
abstract: The mechanisms of action of many CNS drugs have been studied extensively on the level of their target proteins, but the effects of these compounds on the level of complex CNS networks that are composed of different types of excitatory and inhibitory neurons are not well understood. Many currently used anticonvulsant drugs are known to exert potent use-dependent blocking effects on voltage-gated Na(+) channels, which are thought to underlie the inhibition of pathological high-frequency firing. However, some GABAergic inhibitory neurons are capable of firing at very high rates, suggesting that these anticonvulsants should cause impaired GABAergic inhibition. We have, therefore, studied the effects of anticonvulsant drugs acting via use-dependent block of voltage-gated Na(+) channels on GABAergic inhibitory micronetworks in the rodent hippocampus. We find that firing of pyramidal neurons is reliably inhibited in a use-dependent manner by the prototypical Na(+) channel blocker carbamazepine. In contrast, a combination of intrinsic and synaptic properties renders synaptically driven firing of interneurons essentially insensitive to this anticonvulsant. In addition, a combination of voltage imaging and electrophysiological experiments reveal that GABAergic feedforward and feedback inhibition is unaffected by carbamazepine and additional commonly used Na(+) channel-acting anticonvulsants, both in control and epileptic animals. Moreover, inhibition in control and epileptic rats recruited by in vivo activity patterns was similarly unaffected. These results suggest that sparing of inhibition is an important principle underlying the powerful reduction of CNS excitability exerted by anticonvulsant drugs.
authors.affiliation: Laboratory for Experimental Epileptology and Cognition Research and Department of Epileptology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Leonie
authors.initials: L
authors.lastname: Pothmann
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen e.V., 53175 Bonn, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Müller
authors.affiliation: MTA-SZTE Research Group for Cortical Microcircuits, Department of Physiology, Anatomy, and Neuroscience, University of Szeged, Szeged H-6726, Hungary, and.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Averkin
authors.affiliation: Instituto Cajal, CSIC, 37. 28002 Madrid, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Bellistri
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen e.V., 53175 Bonn, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Miklitz
authors.affiliation: Laboratory for Experimental Epileptology and Cognition Research and Department of Epileptology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Mischa
authors.initials: M
authors.lastname: Uebachs
authors.affiliation: Department of Epileptology, University of Bonn, 53127 Bonn, Germany, Deutsches Zentrum für Neurodegenerative Erkrankungen e.V., 53175 Bonn, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Remy
authors.affiliation: Instituto Cajal, CSIC, 37. 28002 Madrid, Spain.
authors.forename: Liset
authors.initials: L
authors.lastname: Menendez de la Prida
authors.affiliation: Laboratory for Experimental Epileptology and Cognition Research and Department of Epileptology, University of Bonn, 53127 Bonn, Germany, Deutsches Zentrum für Neurodegenerative Erkrankungen e.V., 53175 Bonn, Germany, Heinz.beck@ukb.uni-bonn.de.
authors.forename: Heinz
authors.initials: H
authors.lastname: Beck
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D001703:Biophysics; D002220:Carbamazepine / Q000494:pharmacology*; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004827:Epilepsy / Q000139:chemically induced / Q000473:pathology; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D007608:Kainic Acid / Q000633:toxicity; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D009415:Nerve Net / Q000187:drug effects*; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010862:Pilocarpine / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D015222:Sodium Channels; D010862:Pilocarpine; D002220:Carbamazepine; D007608:Kainic Acid
keywords: anticonvulsants; carbamazepine; epilepsy; inhibition; interneurons