The K+/Cl- co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation

Nature. 1999 Jan 21;397(6716):251-5. doi: 10.1038/16697.


GABA (gamma-aminobutyric acid) is the main inhibitory transmitter in the adult brain, and it exerts its fast hyperpolarizing effect through activation of anion (predominantly Cl-)-permeant GABA(A) receptors. However, during early neuronal development, GABA(A)-receptor-mediated responses are often depolarizing, which may be a key factor in the control of several Ca2+-dependent developmental phenomena, including neuronal proliferation, migration and targeting. To date, however, the molecular mechanism underlying this shift in neuronal electrophysiological phenotype is unknown. Here we show that, in pyramidal neurons of the rat hippocampus, the ontogenetic change in GABA(A)-mediated responses from depolarizing to hyperpolarizing is coupled to a developmental induction of the expression of the neuronal (Cl-)-extruding K+/Cl- co-transporter, KCC2. Antisense oligonucleotide inhibition of KCC2 expression produces a marked positive shift in the reversal potential of GABAA responses in functionally mature hippocampal pyramidal neurons. These data support the conclusion that KCC2 is the main Cl- extruder to promote fast hyperpolarizing postsynaptic inhibition in the brain.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Southern
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cell Differentiation
  • Chlorides / metabolism
  • Electrophysiology
  • GABA Agonists / pharmacology
  • Gene Expression Regulation, Developmental
  • Guinea Pigs
  • Hippocampus / cytology
  • Hippocampus / embryology
  • Hippocampus / metabolism
  • In Vitro Techniques
  • K Cl- Cotransporters
  • Muscimol / pharmacology
  • Potassium / metabolism
  • Pyramidal Cells / cytology
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / physiology*
  • RNA, Messenger / analysis
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Symporters*
  • gamma-Aminobutyric Acid / physiology*


  • Carrier Proteins
  • Chlorides
  • GABA Agonists
  • RNA, Messenger
  • Symporters
  • Muscimol
  • gamma-Aminobutyric Acid
  • Potassium