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The Journal of Neuroscience, May 12, 2004, 24(19):4683-4691; doi:10.1523/JNEUROSCI.5265-03.2004

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Cellular/Molecular
Mechanism of Activity-Dependent Downregulation of the Neuron-Specific K-Cl Cotransporter KCC2

Claudio Rivera,^1,2 Juha Voipio,¹ Judith Thomas-Crusells,² Hong Li,^1,2 Zsuzsa Emri,¹ Sampsa Sipilä,¹ John A. Payne,³ Liliana Minichiello,⁴ Mart Saarma,² and Kai Kaila¹

¹Department of Biosciences and ²Institute of Biotechnology, University of Helsinki, Helsinki, FIN-00014 Finland, ³Department of Human Physiology, University of California School of Medicine, Davis, California 95616, and ⁴European Molecular Biology Laboratory, 00016 Monterotondo, Italy

GABA-mediated fast-hyperpolarizing inhibition depends on extrusion of chloride by the neuron-specific K-Cl cotransporter, KCC2. Here we show that sustained interictal-like activity in hippocampal slices downregulates KCC2 mRNA and protein expression in CA1 pyramidal neurons, which leads to a reduced capacity for neuronal Cl^- extrusion. This effect is mediated by endogenous BDNF acting on tyrosine receptor kinase B (TrkB), with down-stream cascades involving both Shc/FRS-2 (src homology 2 domain containing transforming protein/FGF receptor substrate 2) and PLC (phospholipase C)-cAMP response element-binding protein signaling. The plasmalemmal KCC2 has a very high rate of turnover, with a time frame that suggests a novel role for changes in KCC2 expression in diverse manifestations of neuronal plasticity. A downregulation of KCC2 may be a general early response involved in various kinds of neuronal trauma.

Key words: BDNF; neurotrophic factors; intracellular chloride; activity-dependent gene expression; GABAergic transmission; epilepsy

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Received Nov 28, 2003; revised April 7, 2004; accepted April 7, 2004.

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