title: Dynamic changes of depolarizing GABA in a computational model of epileptogenic brain: Insight for Dravet syndrome.
abstract: 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.
authors.affiliation: University Lyon 1, UMR 5558, CRNS, Lyon, France.
authors.forename: P
authors.initials: P
authors.lastname: Kurbatova
authors.affiliation: UMR 1099, Inserm-University Rennes1, LTSI, Rennes, France.
authors.forename: F
authors.initials: F
authors.lastname: Wendling
authors.affiliation: UMR 1129, Inserm-Paris Descartes University-CEA, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Kaminska
authors.affiliation: Pediatric Neurology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Firenze, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Rosati
authors.affiliation: UMR 1129, Inserm-Paris Descartes University-CEA, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Nabbout
authors.affiliation: Pediatric Neurology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Firenze, Italy; IRCCS Fondazione Stella Maris, Pisa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Guerrini
authors.affiliation: UMR 1129, Inserm-Paris Descartes University-CEA, Paris, France.
authors.forename: O
authors.initials: O
authors.lastname: Dulac
authors.affiliation: UMR 1129, Inserm-Paris Descartes University-CEA, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Pons
authors.affiliation: Hôpital Louis Pradel, Centre d'Investigation Clinique, INSERM CIC201/UMR5558, Bron, France; CHU Lyon, Service de Pharmacologie Clinique, Lyon, France; University Lyon 1, UMR 5558, CRNS, Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Cornu
authors.affiliation: CHU Lyon, Service de Pharmacologie Clinique, Lyon, France; University Lyon 1, UMR 5558, CRNS, Lyon, France.
authors.forename: P
authors.initials: P
authors.lastname: Nony
authors.affiliation: UMR 1129, Inserm-Paris Descartes University-CEA, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Chiron
authors.affiliation: UMR 1099, Inserm-University Rennes1, LTSI, Rennes, France.
authors.forename: P
authors.initials: P
authors.lastname: Benquet
mesh_terms: D000293:Adolescent; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D058256:Brain Waves / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000235:genetics / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008959:Models, Neurological; D009154:Mutation / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics; D009433:Neural Inhibition / Q000187:drug effects; D017966:Pyramidal Cells / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human; D005680:gamma-Aminobutyric Acid
keywords: Depolarizing GABA; Dravet; EEG; Epilepsy; Excitatory GABA; Fast-onset; Glutamate; Interneuron; SCN1A; Seizure; Shunting inhibition; Stiripentol