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Lability of GABA A receptor function in human partial epilepsy: Possible relationship to hypometabolism
Author(s) -
Pumain René,
Ahmed Mounia Sid,
Kurcewicz Irène,
Trottier Suzanne,
Louvel Jacques,
Turak Baris,
Devaux Bertrand,
Laschet Jacques
Publication year - 2008
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1167.2008.01845.x
Subject(s) - gabaergic , ictal , ketogenic diet , epilepsy , endogeny , endocrinology , medicine , glycolysis , phosphorylation , biology , gamma aminobutyric acid , neuroscience , chemistry , biochemistry , receptor , metabolism , inhibitory postsynaptic potential
SummaryThe function of the γ‐aminobutyric acid type A receptor (GABAAR) 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 GABAAR 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 GABAAR 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 GABAAR endogenous phosphorylation and should contribute to restoration of GABAergic inhibition in the epileptogenic zone.