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Articles, Neurobiology of Disease

Function of Inhibitory Micronetworks Is Spared by Na+ Channel-Acting Anticonvulsant Drugs

Leonie Pothmann, Christina Müller, Robert G. Averkin, Elisa Bellistri, Carolin Miklitz, Mischa Uebachs, Stefan Remy, Liset Menendez de la Prida and Heinz Beck
Journal of Neuroscience 16 July 2014, 34 (29) 9720-9735; DOI: https://doi.org/10.1523/JNEUROSCI.2395-13.2014
Leonie Pothmann
1Laboratory for Experimental Epileptology and Cognition Research and
2Department of Epileptology, University of Bonn, 53127 Bonn, Germany,
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Christina Müller
3Deutsches Zentrum für Neurodegenerative Erkrankungen e.V., 53175 Bonn, Germany,
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Robert G. Averkin
4MTA-SZTE Research Group for Cortical Microcircuits, Department of Physiology, Anatomy, and Neuroscience, University of Szeged, Szeged H-6726, Hungary, and
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Elisa Bellistri
5Instituto Cajal, CSIC, 37. 28002 Madrid, Spain
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Carolin Miklitz
3Deutsches Zentrum für Neurodegenerative Erkrankungen e.V., 53175 Bonn, Germany,
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Mischa Uebachs
1Laboratory for Experimental Epileptology and Cognition Research and
2Department of Epileptology, University of Bonn, 53127 Bonn, Germany,
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Stefan Remy
2Department of Epileptology, University of Bonn, 53127 Bonn, Germany,
3Deutsches Zentrum für Neurodegenerative Erkrankungen e.V., 53175 Bonn, Germany,
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Liset Menendez de la Prida
5Instituto Cajal, CSIC, 37. 28002 Madrid, Spain
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Heinz Beck
1Laboratory for Experimental Epileptology and Cognition Research and
2Department of Epileptology, University of Bonn, 53127 Bonn, Germany,
3Deutsches Zentrum für Neurodegenerative Erkrankungen e.V., 53175 Bonn, Germany,
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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.

  • anticonvulsants
  • carbamazepine
  • epilepsy
  • inhibition
  • interneurons
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The Journal of Neuroscience: 34 (29)
Journal of Neuroscience
Vol. 34, Issue 29
16 Jul 2014
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Function of Inhibitory Micronetworks Is Spared by Na+ Channel-Acting Anticonvulsant Drugs
Leonie Pothmann, Christina Müller, Robert G. Averkin, Elisa Bellistri, Carolin Miklitz, Mischa Uebachs, Stefan Remy, Liset Menendez de la Prida, Heinz Beck
Journal of Neuroscience 16 July 2014, 34 (29) 9720-9735; DOI: 10.1523/JNEUROSCI.2395-13.2014

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Function of Inhibitory Micronetworks Is Spared by Na+ Channel-Acting Anticonvulsant Drugs
Leonie Pothmann, Christina Müller, Robert G. Averkin, Elisa Bellistri, Carolin Miklitz, Mischa Uebachs, Stefan Remy, Liset Menendez de la Prida, Heinz Beck
Journal of Neuroscience 16 July 2014, 34 (29) 9720-9735; DOI: 10.1523/JNEUROSCI.2395-13.2014
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Keywords

  • anticonvulsants
  • carbamazepine
  • epilepsy
  • inhibition
  • interneurons

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