期刊
JOURNAL OF PHYSIOLOGY-LONDON
卷 588, 期 9, 页码 1527-1540出版社
WILEY
DOI: 10.1113/jphysiol.2009.181826
关键词
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资金
- Academy of Finland
- University of Helsinki Research Funds
- Sigrid Juselius Foundation
- [EPICURE/EFP6-037315]
GABAergic excitatory [K+](o) transients can be readily evoked in the mature rat hippocampus by intense activation of GABA(A) receptors (GABA(A)Rs). Here we show that these [K+](o) responses induced by high-frequency stimulation or GABA(A) agonist application are generated by the neuronal K+-Cl- cotransporter KCC2 and that the transporter-mediated KCl extrusion is critically dependent on the bicarbonate-driven accumulation of Cl- in pyramidal neurons. The mechanism underlying GABAergic [K+](o) transients was studied in CA1 stratum pyramidale using intracellular sharp microelectrodes and extracellular ion-sensitive microelectrodes. The evoked [K+](o) transients, as well as the associated afterdischarges, were strongly suppressed by 0.5-1 mm furosemide, a KCl cotransport inhibitor. Importantly, the GABA(A)R-mediated intrapyramidal accumulation of Cl-, as measured by monitoring the reversal potential of fused IPSPs, was unaffected by the drug. It was further confirmed that the reduction in the [K+](o) transients was not due to effects of furosemide on the Na+-dependent K+-Cl- cotransporter NKCC1 or on intraneuronal carbonic anhydrase activity. Blocking potassium channels by Ba2+ enhanced [K+](o) transients whereas pyramidal cell depolarizations were attenuated in further agreement with a lack of contribution by channel-mediated K+ efflux. The key role of the GABA(A)R channel-mediated anion fluxes in the generation of the [K+](o) transients was examined in experiments where bicarbonate was replaced with formate. This anion substitution had no significant effect on the rate of Cl- accumulation, [K+](o) response or afterdischarges. Our findings reveal a novel excitatory mode of action of KCC2 that can have substantial implications for the role of GABAergic transmission during ictal epileptiform activity.
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