Abstracts

Rationale: Dysregulation of GABAergic transmission is suspected to underlie epileptogenicity of malformations of cortical development through alterations of chloride co-transporters expression Methods: Electrophysiological recordings of human cortical slices from 11 pediatric patients operated from a FCD were performed in vitro on a Multi Electrode Array (120 contacts – MultiChannel Systems), under physiologic conditions, or after pharmacological modulation of GABAergic signaling. Immuno-staining for chloride co-transporter (KCC2) or interneurons (GAD, PV), were done on the same slices, in order to correlate electro physiological and histological abnormalities. Results: FCD slices retain intrinsic epileptogenicity. 36/47 slices displayed spontaneous interictal discharges, along a pattern specific to the histological subtypes. Ictal discharges were generated in hyper excitable conditions in 6/8 patients in the areas producing spontaneous interictal discharges, with a transition to seizure involving the emergence of Pre Ictal Discharges. Interictal discharges were sustained by GABergic signaling as Picrotoxin stopped them in 2/3 slices. Blockade of NKCC1 Cl- co-transporters with 10 microM Bumetanide controled interictal discharges in 9/12 cases. Immuno-staining showed both a reduction of KCC2 immunostaining and a reduction of PV-GAD 67 Interneurons in areas generating interictal discharges as compared to “silent” areas. Conclusions: Spontaneous interictal discharges may be mediated by paradoxical depolarization of pyramidal cells by interneurons, related to altered chloride co-transporters expression. This may be an alternative target for the research of new antiepileptic drugs. Funding: none