Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy.
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 approximately 30% of CaMKIIalpha (calcium/calmodulin-dependent protein kinase IIalpha)-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.
Huberfeld
Gilles
G
INSERM U739, Faculté de Médecine Pitié-Salpêtrière, Université Pierre et Marie Curie Paris 6, IFR70, CHU Pitié-Salpêtrière, 75013 Paris, France. gilles.huberfeld@chups.jussieu.fr
Wittner
Lucia
L
Clemenceau
Stéphane
S
Baulac
Michel
M
Kaila
Kai
K
Miles
Richard
R
Rivera
Claudio
C
D000328:Adult; D000818:Animals; D002712:Chlorides / Q000502:physiology*; D004833:Epilepsy, Temporal Lobe / Q000473:pathology / Q000503:physiopathology*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D008253:Macaca mulatta; D008875:Middle Aged; D015398:Signal Transduction / Q000502:physiology*; D028021:Sodium-Potassium-Chloride Symporters / Q000502:physiology; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*; D000096922:K Cl- Cotransporters
D002712:Chlorides; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C578877:SLC12A2 protein, human