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 journalArticle

342 Scopus citations

Abstract

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
Volume24
Issue number19
DOIs
StatePublished - May 12 2004
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

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    Rivera, C., Voipio, J., Thomas-Crusells, J., Li, H., Emri, Z., Sipilä, S., Payne, J. A., Minichiello, L., Saarma, M., & Kaila, K. (2004). Mechanism of activity-dependent downregulation of the neuron-specific K-Cl cotransporter KCC2. Journal of Neuroscience, 24(19), 4683-4691. https://doi.org/10.1523/JNEUROSCI.5265-03.2004