title: Cortical GABAergic excitation contributes to epileptic activities around human glioma.
abstract: Brain gliomas are highly epileptogenic. Excitatory glutamatergic mechanisms are involved in the generation of epileptic activities in the neocortex surrounding gliomas. However, chloride homeostasis is known to be perturbed in glioma cells. Thus, the contribution of γ-aminobutyric acidergic (GABAergic) mechanisms that depend on intracellular chloride merits closer study. We studied the occurrence, networks, cells, and signaling basis of epileptic activities in neocortical slices from the peritumoral surgical margin resected around human brain gliomas. Postoperative glioma tissue from 69% of patients spontaneously generated interictal-like discharges, synchronized, with a high-frequency oscillation signature, in superficial layers of neocortex around areas of glioma infiltration. Interictal-like events depended both on glutamatergic AMPA receptor-mediated transmission and on depolarizing GABAergic signaling. GABA released by interneurons depolarized 65% of pyramidal cells, in which chloride homeostasis was perturbed because of changes in expression of neuronal chloride cotransporters: KCC2 (K-Cl cotransporter 2) was reduced by 42% and expression of NKCC1 (Na-K-2Cl cotransporter 1) increased by 144%. Ictal-like activities were initiated by convulsant stimuli exclusively in these epileptogenic areas. This study shows that epileptic activities are sustained by excitatory effects of GABA in human peritumoral neocortex, as reported in temporal lobe epilepsies, suggesting that both glutamate and GABA signaling and cellular chloride regulation processes, all also involved in oncogenesis as already shown, induce an imbalance between synaptic excitation and inhibition underlying epileptic discharges in glioma patients. Thus, the control of chloride in neurons and glioma cells may provide a therapeutic target for patients with epileptogenic gliomas.
authors.affiliation: Institut du Cerveau et de la Moelle Epinière, INSERM UMRS975, CNRS UMR7225, Université Pierre et Marie Curie (UPMC), Paris, France.|Service de Neurochirurgie, Centre Hospitalier Sainte-Anne, Paris, France.|Université Paris Descartes, France.
authors.forename: Johan
authors.initials: J
authors.lastname: Pallud
authors.affiliation: Institut du Cerveau et de la Moelle Epinière, INSERM UMRS975, CNRS UMR7225, Université Pierre et Marie Curie (UPMC), Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Le Van Quyen
authors.affiliation: Service de Neuropathologie, Centre Hospitalo-Universitaire Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Bielle
authors.affiliation: INMED, Parc Scientifique de Luminy, Marseille, France.|Université de la Méditerranée, UMR S901 Aix-Marseille Université, Marseille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pellegrino
authors.affiliation: Service de Neuropathologie, Centre Hospitalier Sainte-Anne, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Varlet
authors.affiliation: Institut du Cerveau et de la Moelle Epinière, INSERM UMRS975, CNRS UMR7225, Université Pierre et Marie Curie (UPMC), Paris, France.
authors.forename: Noemie
authors.initials: N
authors.lastname: Cresto
authors.affiliation: Institut du Cerveau et de la Moelle Epinière, INSERM UMRS975, CNRS UMR7225, Université Pierre et Marie Curie (UPMC), Paris, France.|Unité d'Epileptologie, Centre Hospitalo-Universitaire Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Baulac
authors.affiliation: Service de Neuropathologie, Centre Hospitalo-Universitaire Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Duyckaerts
authors.affiliation: INMED, Parc Scientifique de Luminy, Marseille, France.|Université de la Méditerranée, UMR S901 Aix-Marseille Université, Marseille, France.
authors.forename: Nazim
authors.initials: N
authors.lastname: Kourdougli
authors.affiliation: INMED, Parc Scientifique de Luminy, Marseille, France.|Université de la Méditerranée, UMR S901 Aix-Marseille Université, Marseille, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Chazal
authors.affiliation: Service de Neurochirurgie, Centre Hospitalier Sainte-Anne, Paris, France.|Université Paris Descartes, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Devaux
authors.affiliation: INMED, Parc Scientifique de Luminy, Marseille, France.|Université de la Méditerranée, UMR S901 Aix-Marseille Université, Marseille, France.|Neuroscience Center, University of Helsinki, Finland.
authors.forename: Claudio
authors.initials: C
authors.lastname: Rivera
authors.affiliation: Institut du Cerveau et de la Moelle Epinière, INSERM UMRS975, CNRS UMR7225, Université Pierre et Marie Curie (UPMC), Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Miles
authors.affiliation: Institut du Cerveau et de la Moelle Epinière, INSERM UMRS975, CNRS UMR7225, Université Pierre et Marie Curie (UPMC), Paris, France.|Service de Neurochirurgie, Centre Hospitalo-Universitaire Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Capelle
authors.affiliation: Institut du Cerveau et de la Moelle Epinière, INSERM UMRS975, CNRS UMR7225, Université Pierre et Marie Curie (UPMC), Paris, France.|Service de Neuropathologie, Centre Hospitalo-Universitaire Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.|Unité d'Epileptologie, Centre Hospitalo-Universitaire Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.|Département de Neurophysiologie, UPMC, Centre Hospitalo-Universitaire Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Huberfeld
mesh_terms: D000200:Action Potentials; D001932:Brain Neoplasms / Q000473:pathology / Q000503:physiopathology*; D002712:Chlorides / Q000378:metabolism; D004827:Epilepsy / Q000473:pathology / Q000503:physiopathology*; D005910:Glioma / Q000473:pathology / Q000503:physiopathology*; D005971:Glutamates / Q000378:metabolism; D006801:Humans; D007395:Interneurons / Q000473:pathology; D019579:Neocortex / Q000473:pathology / Q000503:physiopathology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D002712:Chlorides; D005971:Glutamates; D005680:gamma-Aminobutyric Acid