Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition

Neuron. 2001 May;30(2):515-24. doi: 10.1016/s0896-6273(01)00297-5.

Abstract

Synaptic inhibition by GABA(A) and glycine receptors, which are ligand-gated anion channels, depends on the electrochemical potential for chloride. Several potassium-chloride cotransporters can lower the intracellular chloride concentration [Cl(-)](i), including the neuronal isoform KCC2. We show that KCC2 knockout mice died immediately after birth due to severe motor deficits that also abolished respiration. Sciatic nerve recordings revealed abnormal spontaneous electrical activity and altered spinal cord responses to peripheral electrical stimuli. In the spinal cord of wild-type animals, the KCC2 protein was found at inhibitory synapses. Patch-clamp measurements of embryonic day 18.5 spinal cord motoneurons demonstrated an excitatory GABA and glycine action in the absence, but not in the presence, of KCC2, revealing a crucial role of KCC2 for synaptic inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Animals, Newborn
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Embryo, Mammalian
  • Embryonic and Fetal Development
  • Gene Expression Regulation, Developmental
  • Glycine / pharmacology
  • Hypoxia / genetics
  • Hypoxia / physiopathology
  • Mice
  • Mice, Knockout
  • Motor Neurons / drug effects
  • Motor Neurons / physiology*
  • Patch-Clamp Techniques
  • Potassium / metabolism
  • Protein Isoforms / deficiency
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Sodium / metabolism
  • Symporters*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*
  • Tetrodotoxin / pharmacology
  • gamma-Aminobutyric Acid / pharmacology

Substances

  • Carrier Proteins
  • Protein Isoforms
  • Symporters
  • potassium-chloride symporters
  • Tetrodotoxin
  • gamma-Aminobutyric Acid
  • Sodium
  • Potassium
  • Glycine