Expression of the KCl cotransporter KCC2 parallels neuronal maturation and the emergence of low intracellular chloride

Abstract

Fast synaptic inhibition in the adult central nervous system (CNS) is mediated by GABA and glycine. During early development GABA acts as an excitatory neurotransmitter, which is deemed to be important for the maturation of the CNS. During development GABAergic responses undergo a switch from excitatory to inhibitory. This switch is correlated with upregulation of KCC2, the neuronal isoform of the potassium-chloride cotransporter family. KCC2 lowers the intraneuronal chloride concentration below its electrochemical equilibrium. KCC2 activity is thought to depend on phosphorylation by endogenous tyrosine kinases. Here, we analyzed the expression pattern of KCC2 during murine embryonic and postnatal development by in situ hybridization and Western blot analysis. KCC2 expression paralleled neuronal differentiation and preceded the decline of the GABA reversal potential (EGABA) in spinal cord motoneurons and hippocampal pyramidal cells. The adult inhibitory response to GABA was established earlier in the spinal cord than in the hippocampus. Phosphorylated KCC2 protein was already present early in development when the functional GABA switch had not yet occurred. Thus, tyrosine-phosphorylation seems to be less important than the transcriptional upregulation of KCC2.