title: Dysfunction of GABAA receptor glycolysis-dependent modulation in human partial epilepsy.
abstract: A reduction in GABAergic neurotransmission has been put forward as a pathophysiological mechanism for human epilepsy. However, in slices of human epileptogenic neocortex, GABAergic inhibition can be clearly demonstrated. In this article we present data showing an increase in the functional lability of GABAergic inhibition in epileptogenic tissue compared with nonepileptogenic human tissue. We have previously shown that the glycolytic enzyme GAPDH is the kinase involved in the glycolysis-dependent endogenous phosphorylation of the alpha1-subunit of GABA(A) receptor, a mechanism necessary for maintaining GABA(A) function. In human epileptogenic cortex obtained during curative surgery of patients with partial seizures, we demonstrate an intrinsic deficiency of GABA(A) receptor endogenous phosphorylation resulting in an increased lability of GABAergic currents in neurons isolated from this tissue when compared with neurons from nonepileptogenic human tissue. This feature was not related to a reduction in the number of GABA(A) receptor alpha1-subunits in the epileptogenic tissue as measured by [(3)H]flunitrazepam photoaffinity labeling. Maintaining the receptor in a phosphorylated state either by favoring the endogenous phosphorylation or by inhibiting a membrane-associated phosphatase is needed to sustain GABA(A) receptor responses in epileptogenic cortex. The increased functional lability induced by the deficiency in phosphorylation can account for transient GABAergic disinhibition favoring seizure initiation and propagation. These findings imply new therapeutic approaches and suggest a functional link to the regional cerebral glucose hypometabolism observed in patients with partial epilepsy, because the dysfunctional GABAergic mechanism depends on the locally produced glycolytic ATP.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 573, F-75014 Paris, France. jacques.laschet@broca.inserm.fr
authors.forename: Jacques J
authors.initials: JJ
authors.lastname: Laschet
authors.forename: Irène
authors.initials: I
authors.lastname: Kurcewicz
authors.forename: Frédéric
authors.initials: F
authors.lastname: Minier
authors.forename: Suzanne
authors.initials: S
authors.lastname: Trottier
authors.forename: Jamila
authors.initials: J
authors.lastname: Khallou-Laschet
authors.forename: Jacques
authors.initials: J
authors.lastname: Louvel
authors.forename: Sylvain
authors.initials: S
authors.lastname: Gigout
authors.forename: Baris
authors.initials: B
authors.lastname: Turak
authors.forename: Arnaud
authors.initials: A
authors.lastname: Biraben
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Scarabin
authors.forename: Bertrand
authors.initials: B
authors.lastname: Devaux
authors.forename: Patrick
authors.initials: P
authors.lastname: Chauvel
authors.forename: René
authors.initials: R
authors.lastname: Pumain
mesh_terms: D002540:Cerebral Cortex / Q000378:metabolism*; D004828:Epilepsies, Partial / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D005445:Flunitrazepam; D006019:Glycolysis; D006801:Humans; D008297:Male; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011963:Receptors, GABA-A / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D014316:Tritium
chemical_list: D011963:Receptors, GABA-A; D014316:Tritium; D005445:Flunitrazepam