The Dual Roles of GABA in Seizures and Epilepsy Generate More Excitement

Abstract

Anomalous Levels of Cl– Transporters in the Hippocampal Subiculum from Temporal Lobe Epilepsy Patients Make GABA Excitatory. Palma E, Amici M, Sobrero F, Spinelli G, Di Angelantonio S, Ragozzino D, Mascia A, Scoppetta C, Esposito V, Miledi R, Eusebi F. Proc Natl Acad Sci USA 2006;103:8465–8468. Erratum in Proc Natl Acad Sci USA 2006;103:11814. 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 reverse transcription polymerase chain reaction (RT-PCR) analyses of the mRNAs extracted from the human TLE-associated brain regions revealed an upregulation of NKCC1 mRNA and a downregulation 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 GABAA 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 EGABA more negative in oocytes injected with membranes from TLE hippocampal subiculum, matching the EGABA 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. The authors note that the last sentence of the abstract should read: “We conclude that the anomalous expression of both Cl– transporters, NKCC1 and KCC2, 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. This error does not affect the conclusions of the article. Epileptogenic Actions of GABA and Fast Oscillations in the Developing Hippocampus. Khalilov I, Le Van Quyen M, Gozlan H, Ben-Ari Y. Neuron 2005;48:787–796. GABA excites immature neurons and inhibits adult ones, but whether this contributes to seizures in the developing brain is not known. We now report that in the developing, but not the adult, hippocampus, seizures beget seizures only if GABAergic synapses are functional. In the immature hippocampus, seizures generated with functional GABAergic synapses include fast oscillations that are required to transform a naive network to an epileptic one: blocking GABA receptors prevents the long-lasting sequels of seizures. In contrast, in adult neurons, full blockade of GABA(A) receptors generates epileptogenic high-frequency seizures. Therefore, purely glutamatergic seizures are not epileptogenic in the developing hippocampus. We suggest that the density of glutamatergic synapses is not sufficient for epileptogenesis in immature neurons; excitatory GABAergic synapses are required for that purpose. We suggest that the synergistic actions of GABA and NMDA receptors trigger the cascades involved in epileptogenesis in the developing hippocampus.