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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 PLCgamma (phospholipase Cgamma)-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.

Original publication




Journal article


J Neurosci

Publication Date





4683 - 4691


Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Animals, Binding Sites, Biotinylation, Brain-Derived Neurotrophic Factor, Cell Membrane, Chlorides, Cyclic AMP Response Element-Binding Protein, Down-Regulation, Hippocampus, In Vitro Techniques, Magnesium, Mice, Mice, Mutant Strains, Neurons, Phospholipase C gamma, Phosphorylation, Pyramidal Cells, RNA, Messenger, Rats, Rats, Wistar, Receptor, trkB, Shc Signaling Adaptor Proteins, Signal Transduction, Src Homology 2 Domain-Containing, Transforming Protein 1, Symporters, Synaptic Transmission, Type C Phospholipases