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The Journal of Neuroscience, September 12, 2007, 27(37):9866-9873; doi:10.1523/JNEUROSCI.2761-07.2007

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Neurobiology of Disease
Perturbed Chloride Homeostasis and GABAergic Signaling in Human Temporal Lobe Epilepsy

Gilles Huberfeld,^1,2,3 * Lucia Wittner,^1,4 * Stéphane Clemenceau,^1,2 Michel Baulac,^1,2 Kai Kaila,^5,6 Richard Miles,¹ and Claudio Rivera⁷

¹INSERM U739, ²Epilepsy Unit, and ³Laboratoire de Neurophysiologie, Faculté de Médecine Pitié-Salpêtrière, Université Pierre et Marie Curie Paris 6, IFR70, CHU Pitié-Salpêtrière, 75013 Paris, France, ⁴Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083, Budapest, Hungary, and ⁵Department of Biological and Environmental Sciences, ⁶Neuroscience Center, and ⁷Institute of Biotechnology, University of Helsinki, FI-00014, Helsinki, Finland

Correspondence should be addressed to Dr. Gilles Huberfeld, INSERM U739, Université Pierre et Marie Curie Paris 6, CHU Pitié-Salpêtrière, 105 Bd de l'Hôpital, 75013 Paris, France. Email: gilles.huberfeld{at}chups.jussieu.fr

Changes in chloride (Cl^–) homeostasis may be involved in the generation of some epileptic activities. In this study, we asked whether Cl^– homeostasis, and thus GABAergic signaling, is altered in tissue from patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis. Slices prepared from this human tissue generated a spontaneous interictal-like activity that was initiated in the subiculum. Records from a minority of subicular pyramidal cells revealed depolarizing GABA_A receptor-mediated postsynaptic events, indicating a perturbed Cl^– homeostasis. We assessed possible contributions of changes in expression of the potassium–chloride cotransporter KCC2. Double in situ hybridization showed that mRNA for KCC2 was absent from 30% of CaMKII (calcium/calmodulin-dependent protein kinase II)-positive subicular pyramidal cells. Combining intracellular recordings with biocytin-filled electrodes and KCC2 immunochemistry, we observed that all cells that were hyperpolarized during interictal events were immunopositive for KCC2, whereas the majority of depolarized cells were immunonegative. Bumetanide, at doses that selectively block the chloride-importing potassium–sodium–chloride cotransporter NKCC1, produced a hyperpolarizing shift in GABA_A reversal potentials and suppressed interictal activity. Changes in Cl^– transporter expression thus contribute to human epileptiform activity, and molecules acting on these transporters may be useful antiepileptic drugs.

Key words: GABA; KCC2; NKCC1; epilepsy; subiculum; bumetanide

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Received Jan. 8, 2007; accepted July 22, 2007.

Correspondence should be addressed to Dr. Gilles Huberfeld, INSERM U739, Université Pierre et Marie Curie Paris 6, CHU Pitié-Salpêtrière, 105 Bd de l'Hôpital, 75013 Paris, France. Email: gilles.huberfeld{at}chups.jussieu.fr

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