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

Abstract

GABA (γ-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 receptors¹. However, during early neuronal development, GABA _A-receptor-mediated responses are often depolarizing²,³, which may be a key factor in the control of several Ca²⁺ −dependent developmental phenomena, including neuronal proliferation, migration and targeting^4,5,6. 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 (ref. 7). Antisense oligonucleotide inhibition of KCC2 expression produces a marked positive shift in the reversal potential of GABA_A 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.