GABAergic transmission underlies interictal epileptogenicity in pediatric FCD

Thomas Blauwblomme (1, 2) , Elena Dossi , Christophe Pellegrino (3) , Emmanuelle Goubert (3) , Beatriz Gal Iglesias , Christian Sainte-Rose (4) , Nathalie Rouach (5) , Rima Nabbout (6) , Gilles Huberfeld (7, 2)

1 INSERM U836, équipe 9, Dynamique des réseaux synchrones épileptiques
2 Inserm U1129 - Épilepsie de l'enfant et plasticité cérébrale
3 INMED - INSERM U1249 - Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université]
4 Service de neurochirurgie pédiatrique [CHU Necker]
5 CIRB - Centre interdisciplinaire de recherche en biologie
6 Département de Neuropédiatrie,
7 CHU Pitié-Salpêtrière [AP-HP]

Objective: Dysregulation of GABAergic transmission has been reported in lesional acquired epilepsies (gliomas, hippocampal sclerosis). We investigated its involvement in a developmental disorder, human Focal Cortical Dysplasia, focusing on chloride regulation driving GABAergic signals. Methods: In vitro recordings of 47 human cortical acute slices from 11 pediatric patients operated from a Focal Cortical Dysplasia were performed on Multi Electrode Array. GABAergic receptors and chloride regulators were pharmacologically modulated. Immunostaining for chloride co-transporter KCC2 and interneurons were performed on recorded slices to correlate electrophysiology and expression patterns. Results: Focal Cortical Dysplasia slices retain intrinsic epileptogenicity. 36/47 slices displayed spontaneous interictal discharges, along with a pattern specific to the histological subtypes. Ictal discharges were induced in proepileptic conditions in 6/8 slices in the areas generating spontaneous interictal discharges, with a transition to seizure involving the emergence of preictal discharges. Interictal discharges were sustained by GABAergic signaling as a GABAA receptors blocker stopped them in 2/3 slices. Blockade of NKCC1 Cl-co-transporters further controlled interictal discharges in 9/12 cases, revealing a Cl-dysregulation affecting actions of GABA. Immunohistochemistry highlighted decreased expression and changes in KCC2 sub-cellular localization and a decrease in the number of GAD67-positive interneurons in regions generating interictal discharges. Interpretation: Altered chloride cotransporters expression and changes in interneuron density in FCD may lead to paradoxical depolarization of pyramidal cells. Spontaneous interictal discharges are consequently mediated by GABAergic signals and targeting chloride regulation in neurons may be considered for the development of new antiepileptic drugs.

Mots clés: Malformations of cortical development; Epilepsy Surgery Abbreviations: CB-PV+: calbindin parvalbumin; FCD: Focal Cortical Dysplasia; KCC2: Potassium-Chloride-co-transporter 2; IID: Interictal Discharges; HFO: High Frequency oscillations; NKCC1: Sodium-Potassium-Chloride-co-transporter 1PID: Preictal Discharges; LVFA: low voltage fast activity; GABA; Cation chloride co-transporter; KCC2; In vitro recordings; SEEG: stereo electro encephalography; Focal Cortical Dysplasia; NKCC1

Domaines: Neurosciences [q-bio.NC]

Thomas Blauwblomme, Elena Dossi, Christophe Pellegrino, Emmanuelle Goubert, Beatriz Gal Iglesias, et al.. GABAergic transmission underlies interictal epileptogenicity in pediatric FCD. Annals of Neurology, 2018, ⟨10.1002/ana.25403⟩. ⟨hal-01971710⟩