The K+-Cl cotransporter KCC2 promotes GABAergic excitation in the mature rat hippocampus

J Physiol. 2010 May 1;588(Pt 9):1527-40. doi: 10.1113/jphysiol.2009.181826. Epub 2010 Mar 8.


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 Ba(2+) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / pharmacology
  • Barium / pharmacology
  • Bicarbonates / metabolism
  • CA1 Region, Hippocampal / metabolism
  • Carbonic Anhydrase Inhibitors / pharmacology
  • Chlorides / metabolism
  • Diuretics / pharmacology
  • Electric Stimulation
  • Electrophysiology
  • Epilepsy / physiopathology
  • Furosemide / pharmacology
  • GABA Agonists / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / physiology*
  • Hydrogen-Ion Concentration
  • Isonicotinic Acids / pharmacology
  • K Cl- Cotransporters
  • Microelectrodes
  • Potassium / metabolism
  • Potassium / pharmacology
  • Pyramidal Cells / metabolism
  • Rats
  • Receptors, GABA-A / drug effects
  • Receptors, GABA-A / physiology
  • Spectrometry, Fluorescence
  • Symporters / drug effects
  • Symporters / physiology*
  • gamma-Aminobutyric Acid / physiology*


  • Anticonvulsants
  • Bicarbonates
  • Carbonic Anhydrase Inhibitors
  • Chlorides
  • Diuretics
  • GABA Agonists
  • Isonicotinic Acids
  • Receptors, GABA-A
  • Symporters
  • Barium
  • gamma-Aminobutyric Acid
  • Furosemide
  • Potassium
  • isoguvacine