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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 GABAA 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 targeting4,5,6. 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 GABAA-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 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.

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Figure 1: Developmental regulation and neuron-specific expression of the K+/Cl co-transporter KCC2.
Figure 2: Expression of KCC2 mRNA in the developing rat hippocampus revealed by in situ hybridization.
Figure 3: Specific inhibition of KCC2 protein expression by antisense-A PODN and its suppressing effect on hyperpolarizing GABAA-receptor-mediated responses.

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Acknowledgements

We thank F. Edwards, T. Freund and H. Rauvala for comments on this paper. This work was supported by the Academy of Finland (K.K. and M.S.), the Sigrid Juselius Foundation (K.K. and M.S.), the Swedish Council for Natural Sciences (C.R.) and Hibbard E. Williams Research Fund, National Institute of Neurological Disorders and Stroke, Epilepsy Foundation of America (J.A.P.).

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Rivera, C., Voipio, J., Payne, J. et al. The K+/Cl co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397, 251–255 (1999). https://doi.org/10.1038/16697

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