Dynamic changes of depolarizing GABA in a computational model of epileptogenic brain: Insight for Dravet syndrome

Abnormal reemergence of depolarizing GABAA current during postnatal brain maturation may play a major role in paediatric epilepsies, Dravet syndrome (DS) being among the most severe. To study the impact of depolarizing GABA onto distinct patterns of EEG activity, we extended a neural mass model as f...

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Veröffentlicht in:Experimental neurology 2016-09, Vol.283 (Pt A), p.57-72
Hauptverfasser: Kurbatova, P., Wendling, F., Kaminska, A., Rosati, A., Nabbout, R., Guerrini, R., Dulac, O., Pons, G., Cornu, C., Nony, P., Chiron, C., Benquet, P.
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Zusammenfassung:Abnormal reemergence of depolarizing GABAA current during postnatal brain maturation may play a major role in paediatric epilepsies, Dravet syndrome (DS) being among the most severe. To study the impact of depolarizing GABA onto distinct patterns of EEG activity, we extended a neural mass model as follows: one sub-population of pyramidal cells was added as well as two sub-populations of interacting interneurons, perisomatic-projecting interneurons (basket-like) with fast synaptic kinetics GABAA (fast, I1) and dendritic-projecting interneurons with slow synaptic kinetics GABAA (slow, I2). Basket-like cells were interconnected to reproduce mutual inhibition mechanisms (I1➔I1). The firing rate of interneurons was adapted to mimic the genetic alteration of voltage gated sodium channels found in DS patients, SCN1A+/−. We implemented the “dynamic depolarizing GABAA” mediated post-synaptic potential in the model, as some studies reported that the chloride reversal potential can switch from negative to more positive value depending on interneuron activity. The “shunting inhibition” promoted by GABAA receptor activation was also implemented. We found that increasing the proportion of depolarizing GABAA mediated IPSP (I1➔I1 and I1➔P) only (i.e., other parameters left unchanged) was sufficient to sequentially switch the EEG activity from background to (1) interictal isolated polymorphic epileptic spikes, (2) fast onset activity, (3) seizure like activity and (4) seizure termination. The interictal and ictal EEG patterns observed in 4 DS patients were reproduced by the model via tuning the amount of depolarizing GABAA postsynaptic potential. Finally, we implemented the modes of action of benzodiazepines and stiripentol, two drugs recommended in DS. Both drugs blocked seizure-like activity, partially and dose-dependently when applied separately, completely and with a synergic effect when combined, as has been observed in DS patients. This computational modeling study constitutes an innovative approach to better define the role of depolarizing GABA in infantile onset epilepsy and opens the way for new therapeutic hypotheses, especially in Dravet syndrome. •Excitatory GABA effect was implemented in a computational neural mass model.•Dynamic emergence of depolarizing GABA triggers interictal to ictal transitions.•Results suggest a major role of GABAergic interneurons in seizure onset.•Model reproduces clinical patterns found in a severe infantile epilepsy.
ISSN:0014-4886
1090-2430
DOI:10.1016/j.expneurol.2016.05.037