Is connexin36 critical for GABAergic hypersynchronization in the hippocampus?

Michael Beaumont, Gianmaria Maccaferri*

*Corresponding author for this work

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

In some forms of incurable epilepsies, GABAergic interneurons, which physiologically mediate inhibition in the brain, are thought to mediate excitation. The presence of a specific form of electrical communication between these cells, which is mediated by structures called gap junctions, has been proposed to be involved in the generation of synchronized epileptiform discharges. In support of this hypothesis is the repeated finding in the literature that the drug carbenoxolone, which is an effective blocker of gap junction function, decreases epileptiform activity in models of epilepsy both in vivo and in vitro. Our work challenges this view and highlights additional side-effects of carbenoxolone, which are unrelated to gap junctions, but seem to contribute to its reported antiepileptic activity. A full knowledge of these additional mechanisms is important for the rational development of new molecules to be used in the therapy of epilepsy. Abstract Synchronous bursting of cortical GABAergic interneurons is important in epilepsies associated with excitatory GABAergic signalling. If electrical coupling was critical for the generation of this pathological activity, then the development of selective blockers of connexin36-based interneuronal gap junctions could be of therapeutic value. We have addressed this issue in the 4-aminopyridine model of epilepsy in vitro by comparing GABAergic epileptiform currents and their sensitivity to gap junction blockers in wild-type vs. connexin36 knockout mice. Although electrical coupling was abolished in stratum lacunosum-moleculare interneurons from knockout animals, epileptiform currents were not eliminated. Furthermore, epileptiform currents propagated similarly across hippocampal layers in the two genotypic groups. Blockade of electrical coupling with carbenoxolone suppressed amplitude, frequency and half-width of the epileptiform currents both in wild-type and in knockout animals, whereas mefloquine had no effects. Carbenoxolone also depressed responses to exogenous and synaptic GABA application onto interneurons. We conclude that, in the 4-aminopyridine model of epilepsy in vitro, connexin36 is not critical for the generation of epileptiform discharges in GABAergic networks and that the observed antiepileptic effects of carbenoxolone are likely to be due to blockade of GABAA receptors and not of connexin36-based gap junctions. Lastly, because of its chemical structure and its effects on amplitude and kinetics of GABAergic currents, we tested the hypothesis that carbenoxolone acted via specific sites on GABAA receptors, such as the one mediating the effects of the neurosteroid pregnenolone sulfate, or the allosteric regulatory site of benzodiazepines/β-carbolines. Our results suggest that neither of these is involved.

Original languageEnglish (US)
Pages (from-to)1663-1680
Number of pages18
JournalJournal of Physiology
Volume589
Issue number7
DOIs
StatePublished - Apr 2011

ASJC Scopus subject areas

  • Physiology

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