Mechanism of activity-dependent downregulation of the neuron-specific K-Cl cotransporter KCC2

Claudio Rivera, Juha Voipio, Judith Thomas-Crusells, Hong Li, Zsuzsa Emri, Sampsa Sipilä, John A. Payne, Liliana Minichiello, Mart Saarma, Kai Kaila

Research output: Contribution to journalArticlepeer-review

388 Scopus citations


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 PLCγ (phospholipase Cγ)-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 languageEnglish (US)
Pages (from-to)4683-4691
Number of pages9
JournalJournal of Neuroscience
Issue number19
StatePublished - May 12 2004


  • Activity-dependent gene expression
  • BDNF
  • Epilepsy
  • GABAergic transmission
  • Intracellular chloride
  • Neurotrophic factors

ASJC Scopus subject areas

  • Neuroscience(all)


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