Lability of GABAA receptor function in human partial epilepsy: possible relationship to hypometabolism.
The function of the gamma-aminobutyric acid type A receptor (GABA(A)R) is maintained by endogenous phosphorylation. We have shown that the corresponding kinase is the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), using the locally produced glycolytic ATP. In addition, using cerebral tissue obtained during curative surgery for epilepsy, we showed that both the endogenous phosphorylation and the GABA(A)R function are significantly reduced in the "epileptogenic" cerebral cortex when compared to "control" tissue. This dysfunction likely contributes to seizure generation and/or transition from the interictal to the ictal state. Glucose utilization is decreased in the epileptogenic cortex of patients with partial epilepsy in the interictal state, but the relationship to the disorder remains unclear. We propose that this hypometabolism is related to the deficiency in the endogenous phosphorylation of GABA(A)R and the resulting greater lability of GABAergic inhibition. Several lines of evidences indeed suggest that GABAergic inhibition is costly in terms of metabolic consumption. The deficiency of this glycolysis-dependent mechanism may thus link epileptogenicity to glucose hypometabolism. The antiepileptic effect of ketogenic diets may be mediated by the subsequent rise in the NADH/NAD(+) index, which favors GABA(A)R endogenous phosphorylation and should contribute to restoration of GABAergic inhibition in the epileptogenic zone.
Pumain
René
R
Inserm U894, Centre de Psychiatrie et de Neurosciences, Paris, France. rene.pumain@inserm.fr
Ahmed
Mounia Sid
MS
Kurcewicz
Irène
I
Trottier
Suzanne
S
Louvel
Jacques
J
Turak
Baris
B
Devaux
Bertrand
B
Laschet
Jacques
J
D001921:Brain / Q000378:metabolism*; D055423:Diet, Ketogenic; D004828:Epilepsies, Partial / Q000378:metabolism*; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D011963:Receptors, GABA-A / Q000378:metabolism*
D011963:Receptors, GABA-A; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)