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

Synaptic inhibition by GABA, and glycine receptors, which are ligand-gated anion channels, depends on the electrochemical potential for chloride. Seve ral potassium-chloride cotransporters can lower the intracellular chloride concentration [Cl-](i), including the neuronal isoform KCC2. We show that K CC2 knockout mice died immediately after birth due to severe motor deficits that also abolished respiration. Sciatic nerve recordings revealed abnorma l spontaneous electrical activity and altered spinal cord responses to peri pheral electrical stimuli. In the spinal cord of wild-type animals, the KCC 2 protein was found at inhibitory synapses. Patch-clamp measurements of emb ryonic 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.