Excitatory GABAergic signalling is associated with acquired benzodiazepine resistance in status epilepticus

Burman, R. J.; Calin, A.; Codadu, N. K.; Wright, R.; Newey, S. E.; van den Berg, M.; Lee, J. H.; Parish, R. R.; Wilmshurst, J. M.; Akerman, C. J.; Trevelyan, A. J.; Raimondo, J. V.

doi:10.1101/478594

bioRxiv · 10.1101/478594

Excitatory GABAergic signalling is associated with acquired benzodiazepine resistance in status epilepticus

Burman, R. J.·Calin, A.·Codadu, N. K.·Wright, R.·Newey, S. E.·van den Berg, M.·Lee, J. H.·Parish, R. R.·Wilmshurst, J. M.·Akerman, C. J.·Trevelyan, A. J.·Raimondo, J. V.

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Abstract

Status epilepticus (SE) is defined as a state of unrelenting seizure activity. It is associated with a rapidly rising mortality rate, and thus constitutes a medical emergency. Benzodiazepines, which act as positive modulators of chloride (Cl-) permeable GABAA receptors, are indicated as the first line of treatment, but this is ineffective in many cases. We found that 48% of children presenting with SE were unresponsive to benzodiazepine treatment, and critically, that the duration of SE at the time of treatment is an important predictor of non-responsiveness. We therefore investigated the cellular mechanisms that underlie acquired benzodiazepine resistance, using rodent organotypic brain slices. Removing Mg2+ ions leads to an evolving pattern of epileptiform activity, and eventually to a persistent state of repetitive discharges that strongly resembles clinical EEG recordings of SE. We show that the persistent SE-like activity is associated with a reduction in GABAA receptor conductance and Cl- extrusion capability. We explored the effect on intraneuronal Cl- using both gramicidin, perforated-patch clamp recordings and Cl- imaging. This showed that during SE-like activity, reduced Cl- extrusion capacity was further exacerbated by activity-dependent Cl- loading, resulting in a persistently high intraneuronal Cl-. Consistent with these results, we found that optogenetic stimulation of GABAergic interneurons in the SE-like state, actually enhanced epileptiform activity in a GABAAR dependent manner. Together our findings describe a novel potential mechanism underlying benzodiazepine-resistant SE, with relevance to how this life-threatening condition should be managed in the clinic.

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Burman, R. J., Calin, A., Codadu, N. K., Wright, R., Newey, S. E., van den Berg, M., Lee, J. H., Parish, R. R., Wilmshurst, J. M., Akerman, C. J., Trevelyan, A. J., Raimondo, J. V.. 2018-11-30. Excitatory GABAergic signalling is associated with acquired benzodiazepine resistance in status epilepticus. https://doi.org/10.1101/478594

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