title: Chloride-mediated inhibition of the ictogenic neurones initiating genetically-determined absence seizures.
abstract: Electroclinical investigations in human patients and experimental studies from genetic models demonstrated that spike-and-wave discharges (SWDs) associated with absence seizures have a cortical onset. In the Genetic Absence Epilepsy Rat from Strasbourg (GAERS), SWDs are initiated by the paroxysmal discharges of ictogenic pyramidal neurones located in the deep layers of the somatosensory cortex. However, the cellular and synaptic mechanisms that control the ictal discharges of seizure-initiating neurones remain unclear. Here, by the means of in vivo paired electroencephalographic (EEG) and intracellular recordings in the GAERS cortical focus, we explored the participation of the intracortical inhibitory system in the control of paroxysmal activities in ictogenic neurones. We found that their firing during EEG paroxysms was interrupted by the occurrence of hyperpolarizing synaptic events that reversed in polarity below action potential threshold. Intracellular injection of Cl(-) dramatically increased the amplitude of the paroxysmal depolarizations and the number of generated action potentials, strongly suggesting that the inhibitory synaptic potentials were mediated by GABA(A) receptors. Consistently, we showed that intracellularly recorded GABAergic interneurones fired, during seizures, shortly after (∼+8 ms) the discharge of ictogenic neurones and displayed a rhythmic bursting that coincided with the inhibitory synaptic events in neighbouring pyramidal ictogenic cells. In contrast with other forms of epilepsy, our findings suggest that paroxysmal activities in the cortical pyramidal cells initiating absence seizures are negatively controlled by a feedback Cl(-)-mediated inhibition likely resulting from the fast recurrent activation of intracortical GABAergic interneurones by the ictogenic cells themselves.
authors.affiliation: Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UPMC/INSERM UMR-S 975, CNRS UMR 7225, Hôpital Pitié-Salpêtrière, F-75013, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Chipaux
authors.forename: S
authors.initials: S
authors.lastname: Charpier
authors.forename: P-O
authors.initials: PO
authors.lastname: Polack
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D004195:Disease Models, Animal; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000235:genetics / Q000503:physiopathology*; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D051381:Rats; D011922:Rats, Mutant Strains