GABAergic transmission underlies interictal epileptogenicity in pediatric FCD

Autor: Blauwblomme, Thomas, Dossi, Elena, Pellegrino, Christophe, Goubert, Emmanuelle, Gal Iglesias, Beatriz, Sainte-Rose, Christian, Rouach, Nathalie, Nabbout, Rima, Huberfeld, Gilles
Přispěvatelé: INSERM U836, équipe 9, Dynamique des réseaux synchrones épileptiques, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Service de neurochirurgie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), pellegrino, Christophe
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Annals of Neurology
Annals of Neurology, Wiley, 2018, ⟨10.1002/ana.25403⟩
Annals of Neurology, 2018, ⟨10.1002/ana.25403⟩
ISSN: 0364-5134
1531-8249
DOI: 10.1002/ana.25403⟩
Popis: International audience; 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.
Databáze: OpenAIRE
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