Anomalous levels of Cl- transporters in the hippocampal subiculum from temporal lobe epilepsy patients make GABA excitatory

E. Palma, M. Amici, F. Sobrero, G. Spinelli, S. Di Angelantonio, D. Ragozzino, A. Mascia, C. Scoppetta, V. Esposito, R. Miledi, F. Eusebi

Research output: Contribution to journalArticlepeer-review

Abstract

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- transporter 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 (EGABA) compared with the hippocampus proper or the neocortex. The NKCC1 blocker bumetanide or a temperature decrease of 10°C shifted the GABA-current FGABA 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, KCC1 and NKCC2, 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.

Original languageEnglish
Pages (from-to)8465-8468
Number of pages4
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number22
DOIs
Publication statusPublished - May 30 2006

Keywords

  • Chloride transporter
  • GABA receptors
  • Xenopus oocytes

ASJC Scopus subject areas

  • Genetics
  • General

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