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Dysfunction of ${\rm GABA}_{{\rm A}}$ Receptor Glycolysis-Dependent Modulation in Human Partial Epilepsy

Jacques J. Laschet, Irène Kurcewicz, Frédéric Minier, Suzanne Trottier, Jamila Khallou-Laschet, Jacques Louvel, Sylvain Gigout, Baris Turak, Arnaud Biraben, Jean-Marie Scarabin, Bertrand Devaux, Patrick Chauvel and René Pumain
Proceedings of the National Academy of Sciences of the United States of America
Vol. 104, No. 9 (Feb. 27, 2007), pp. 3472-3477
Stable URL: http://www.jstor.org/stable/25426674
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Dysfunction of
          ${\rm GABA}_{{\rm A}}$
          Receptor Glycolysis-Dependent Modulation in Human Partial Epilepsy
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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 preciously shown that the glycolytic enzyme GAPDH is the kinase involved in the glycolysis-dependent endogenous phosphorylation of the α1-subunit of ${\rm GABA}_{{\rm A}}$ receptor, a mechanism necessary for maintaining ${\rm GABA}_{{\rm A}}$ function. In human epileptogenic cortex obtained during curative surgery of patients with partial seizures, we demonstrate an intrinsic deficiency of ${\rm GABA}_{{\rm A}}$ 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 ${\rm GABA}_{{\rm A}}$ receptor α1-subunits in the epileptogenic tissue as measured by [³H]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 ${\rm GABA}_{{\rm A}}$ 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.

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