Dysfunction of GABAA receptor glycolysis-dependent modulation in human partial epilepsy.
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.
Laschet
Jacques J
JJ
Institut National de la Santé et de la Recherche Médicale, Unité 573, F-75014 Paris, France. jacques.laschet@broca.inserm.fr
Kurcewicz
Irène
I
Minier
Frédéric
F
Trottier
Suzanne
S
Khallou-Laschet
Jamila
J
Louvel
Jacques
J
Gigout
Sylvain
S
Turak
Baris
B
Biraben
Arnaud
A
Scarabin
Jean-Marie
JM
Devaux
Bertrand
B
Chauvel
Patrick
P
Pumain
René
R
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
D011963:Receptors, GABA-A; D014316:Tritium; D005445:Flunitrazepam