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Excitatory GABAergic signalling is associated with benzodiazepine resistance in status epilepticus

Lookup NU author(s): Neela Codadu, Ryley Parrish, Professor Andrew Trevelyan


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© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: epilepticus is defined as a state of unrelenting seizure activity. Generalized convulsive status epilepticus 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 first-line treatment, but this is ineffective in many cases. We found that 48% of children presenting with status epilepticus were unresponsive to benzodiazepine treatment, and critically, that the duration of status epilepticus 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 and acute 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 status epilepticus. We found that diazepam loses its antiseizure efficacy and conversely exacerbates epileptiform activity during this stage of status epilepticus-like activity. Interestingly, a low concentration of the barbiturate phenobarbital had a similar exacerbating effect on status epilepticus-like activity, while a high concentration of phenobarbital was effective at reducing or preventing epileptiform discharges. We then show that the persistent status epilepticus-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 status epilepticus-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 status epilepticus-like state, actually enhanced epileptiform activity in a GABAAR dependent manner. Together our findings describe a novel potential mechanism underlying benzodiazepine-resistant status epilepticus, with relevance to how this life-threatening condition should be managed in the clinic.

Publication metadata

Author(s): Burman RJ, Selfe JS, Lee JH, van den Berg M, Calin A, Codadu NK, Wright R, Newey SE, Parrish RR, Katz AA, Wilmshurst JM, Akerman CJ, Trevelyan AJ, Raimondo JV

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2019

Volume: 142

Issue: 11

Pages: 3482-3501

Online publication date: 23/09/2019

Acceptance date: 11/07/2019

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: NLM (Medline)


DOI: 10.1093/brain/awz283

PubMed id: 31553050


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