Open AccessAnomalous levels of Cl − transporters in the hippocampal subiculum from temporal lobe epilepsy patients make GABA excitatory
Author(s) -
Eleonora Palma,
Mascia Amici,
Fabrizia Sobrero,
Gabriele Spinelli,
Silvia Di Angelantonio,
Davide Ragozzino,
Addolorata Mascia,
C Scoppetta,
Vincenzo Esposito,
Ricardo Miledi,
Fabrizio Eusebi
Publication year - 2006
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0602979103
Subject(s) - subiculum , neocortex , hippocampal formation , cotransporter , hippocampus , neuroscience , epilepsy , chemistry , endocrinology , medicine , gabaa receptor , excitatory postsynaptic potential , biology , microbiology and biotechnology , biophysics , receptor , biochemistry , dentate gyrus , inhibitory postsynaptic potential , organic chemistry , sodium
The mRNA levels of NKCC1, an inwardly directed Na(+), K(+)-2Cl(-) cotransporter that facilitates the accumulation of intracellular Cl(-), and of KCC2, an outwardly directed K(+)-Cl(-) cotransporter that extrudes Cl(-), were studied in surgically resected brain specimens from drug-resistant temporal lobe (TL) epilepsy (TLE) patients. Quantitative RT-PCR analyses of the mRNAs extracted from the human TLE-associated brain regions revealed an up-regulation of NKCC1 mRNA and a down-regulation of KCC2 mRNA in the hippocampal subiculum, compared with the hippocampus proper or the TL neocortex, suggesting an abnormal transcription of Cl(-) transporters in the TLE subiculum. In parallel experiments, cell membranes isolated from the same TLE-associated brain regions were injected into Xenopus oocytes that rapidly incorporated human GABA(A) receptors into their surface membrane. The GABA currents elicited in oocytes injected with membranes from the subiculum had a more depolarized reversal potential (E(GABA)) compared with the hippocampus proper or the neocortex. The NKCC1 blocker bumetanide or a temperature decrease of 10 degrees C shifted the GABA-current E(GABA) more negative in oocytes injected with membranes from TLE hippocampal subiculum, matching the E(GABA) of TL neocortex-injected oocytes. We conclude that the anomalous expression of both Cl(-) transporters, NKCC1 and KCC2 [corrected] in TLE hippocampal subiculum probably causes altered Cl(-) transport in the "epileptic" neurons, as revealed in the microtransplanted Xenopus oocytes, and renders GABA aberrantly "exciting," a feature that may contribute to the precipitation of epileptic seizures.