Hippocampus and epilepsy: Findings from human tissues.
Surgical removal of the epileptogenic zone provides an effective therapy for several focal epileptic syndromes. This surgery offers the opportunity to study pathological activity in living human tissue for pharmacoresistant partial epilepsy syndromes including temporal lobe epilepsies with hippocampal sclerosis, cortical dysplasias, epilepsies associated with tumors and developmental malformations. Slices of tissue from patients with these syndromes retain functional neuronal networks and may generate epileptic activities. The properties of cells in this tissue may not be greatly changed, but excitatory synaptic transmission is often enhanced and GABAergic inhibition is preserved. Typically epileptic activity is not generated spontaneously by the neocortex, whether dysplastic or not, but can be induced by convulsants. The initiation of ictal discharges in the neocortex depends on both GABAergic signaling and increased extracellular potassium. In contrast, a spontaneous interictal-like activity is generated by tissues from patients with temporal lobe epilepsies associated with hippocampal sclerosis. This activity is initiated, not in the hippocampus but in the subiculum, an output region, which projects to the entorhinal cortex. Interictal events seem to be triggered by GABAergic cells, which paradoxically excite about 20% of subicular pyramidal cells while simultaneously inhibiting the majority. Interictal discharges thus depend on both GABAergic and glutamatergic signaling. The depolarizing effects of GABA depend on a pathological elevation in levels of chloride in some subicular cells, similar to those of developmentally immature cells. Such defect is caused by a perturbed expression of the cotransporters regulating intracellular chloride concentration, the importer NKCC1 and the extruder KCC2. Blockade of NKCC1 actions by the diuretic bumetanide restores intracellular chloride and thus hyperpolarizing GABAergic actions and consequently suppressing interictal activity.
Département de neurophysiologie, Sorbonne universités, UPMC - université Paris 06, UPMC, CHU de la Pitié-Salpêtrière, 47-83, boulevard de l'Hôpital, 75013 Paris, France; INSERM Unit U1129 Infantile Epilepsies and Brain Plasticity, University Paris Descartes, Sorbonne Paris Cité, CEA, 12, rue de l'École-de-Médecine, 75006 Paris, France. Electronic address: gilles.huberfeld@upmc.fr.
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Huberfeld
INSERM Unit U1129 Infantile Epilepsies and Brain Plasticity, University Paris Descartes, Sorbonne Paris Cité, CEA, 12, rue de l'École-de-Médecine, 75006 Paris, France; Neurosurgery Department, Necker-Enfants Malades Hospital, University Paris Descartes, PRES Sorbonne Paris Cité, 12, rue de l'École-de-Médecine, 75006 Paris, France.
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Blauwblomme
Inserm U1127, CNRS UMR7225, Sorbonne universités, UPMC - université Paris 6 UMR S1127, Institut du cerveau et de la moelle épinière, 47, boulevard de l'Hôpital, 75013 Paris, France.
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Miles
D004827:Epilepsy / Q000473:pathology* / Q000628:therapy; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D009474:Neurons / Q000473:pathology; D012640:Seizures / Q000473:pathology / Q000503:physiopathology
Epilepsy; GABA(A) receptors; Humain; Human; In vitro; Récépteurs GABA(A); Subiculum; Épilepsie