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

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)9720-9735
Number of pages16
JournalJournal of Neuroscience
Volume34
Issue number29
DOIs
Publication statusPublished - 2014

Fingerprint

Anticonvulsants
Carbamazepine
GABAergic Neurons
Pyramidal Cells
Interneurons
Rodentia
Hippocampus
Neurons
Pharmaceutical Preparations
Proteins

Keywords

  • Anticonvulsants
  • Carbamazepine
  • Epilepsy
  • Inhibition
  • Interneurons

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Pothmann, L., Müller, C., Averkin, R. G., Bellistri, E., Miklitz, C., Uebachs, M., ... Beck, H. (2014). Function of inhibitory micronetworks is spared by Na+ channel-acting anticonvulsant drugs. Journal of Neuroscience, 34(29), 9720-9735. https://doi.org/10.1523/JNEUROSCI.2395-13.2014

Function of inhibitory micronetworks is spared by Na+ channel-acting anticonvulsant drugs. / Pothmann, Leonie; Müller, Christina; Averkin, Robert G.; Bellistri, Elisa; Miklitz, Carolin; Uebachs, Mischa; Remy, Stefan; de la Prida, Liset Menendez; Beck, Heinz.

In: Journal of Neuroscience, Vol. 34, No. 29, 2014, p. 9720-9735.

Research output: Contribution to journalArticle

Pothmann, L, Müller, C, Averkin, RG, Bellistri, E, Miklitz, C, Uebachs, M, Remy, S, de la Prida, LM & Beck, H 2014, 'Function of inhibitory micronetworks is spared by Na+ channel-acting anticonvulsant drugs', Journal of Neuroscience, vol. 34, no. 29, pp. 9720-9735. https://doi.org/10.1523/JNEUROSCI.2395-13.2014
Pothmann, Leonie ; Müller, Christina ; Averkin, Robert G. ; Bellistri, Elisa ; Miklitz, Carolin ; Uebachs, Mischa ; Remy, Stefan ; de la Prida, Liset Menendez ; Beck, Heinz. / Function of inhibitory micronetworks is spared by Na+ channel-acting anticonvulsant drugs. In: Journal of Neuroscience. 2014 ; Vol. 34, No. 29. pp. 9720-9735.
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