Pathophysiological activity and various kinds of traumatic insults are known to have deleterious long-term effects on neuronal Cl− regulation, which can lead to a suppression of fast postsynaptic GABAergic responses. Brain-derived neurotrophic factor (BDNF) increases neuronal excitability through a conjunction of mechanisms that include regulation of the efficacy of GABAergic transmission. Here, we show that exposure of rat hippocampal slice cultures and acute slices to exogenous BDNF or neurotrophin-4 produces a TrkB-mediated fall in the neuron-specific K+–Cl− cotransporter KCC2 mRNA and protein, as well as a consequent impairment in neuronal Cl− extrusion capacity. After kindling-induced seizures in vivo, the expression of KCC2 is down-regulated in the mouse hippocampus with a spatiotemporal profile complementary to the up-regulation of TrkB and BDNF. The present data demonstrate a novel mechanism whereby BDNF/TrkB signaling suppresses chloride-dependent fast GABAergic inhibition, which most likely contributes to the well-known role of TrkB-activated signaling cascades in the induction and establishment of epileptic activity.
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9 December 2002
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December 09 2002
BDNF-induced TrkB activation down-regulates the K+–Cl− cotransporter KCC2 and impairs neuronal Cl− extrusion
Claudio Rivera,
Claudio Rivera
1Department of Biosciences, Division of Animal Physiology
2Institute of Biotechnology, Viikki Biocenter, FIN-00014 University of Helsinki, Helsinki, Finland
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Hong Li,
Hong Li
1Department of Biosciences, Division of Animal Physiology
2Institute of Biotechnology, Viikki Biocenter, FIN-00014 University of Helsinki, Helsinki, Finland
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Judith Thomas-Crusells,
Judith Thomas-Crusells
2Institute of Biotechnology, Viikki Biocenter, FIN-00014 University of Helsinki, Helsinki, Finland
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Hannele Lahtinen,
Hannele Lahtinen
1Department of Biosciences, Division of Animal Physiology
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Tero Viitanen,
Tero Viitanen
1Department of Biosciences, Division of Animal Physiology
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Avtandil Nanobashvili,
Avtandil Nanobashvili
3Section for Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, 221 84 Lund, Sweden
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Zaal Kokaia,
Zaal Kokaia
3Section for Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, 221 84 Lund, Sweden
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Matti S. Airaksinen,
Matti S. Airaksinen
2Institute of Biotechnology, Viikki Biocenter, FIN-00014 University of Helsinki, Helsinki, Finland
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Juha Voipio,
Juha Voipio
1Department of Biosciences, Division of Animal Physiology
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Kai Kaila,
Kai Kaila
1Department of Biosciences, Division of Animal Physiology
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Mart Saarma
Mart Saarma
2Institute of Biotechnology, Viikki Biocenter, FIN-00014 University of Helsinki, Helsinki, Finland
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Claudio Rivera
1Department of Biosciences, Division of Animal Physiology
2Institute of Biotechnology, Viikki Biocenter, FIN-00014 University of Helsinki, Helsinki, Finland
Hong Li
1Department of Biosciences, Division of Animal Physiology
2Institute of Biotechnology, Viikki Biocenter, FIN-00014 University of Helsinki, Helsinki, Finland
Judith Thomas-Crusells
2Institute of Biotechnology, Viikki Biocenter, FIN-00014 University of Helsinki, Helsinki, Finland
Hannele Lahtinen
1Department of Biosciences, Division of Animal Physiology
Tero Viitanen
1Department of Biosciences, Division of Animal Physiology
Avtandil Nanobashvili
3Section for Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, 221 84 Lund, Sweden
Zaal Kokaia
3Section for Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, 221 84 Lund, Sweden
Matti S. Airaksinen
2Institute of Biotechnology, Viikki Biocenter, FIN-00014 University of Helsinki, Helsinki, Finland
Juha Voipio
1Department of Biosciences, Division of Animal Physiology
Kai Kaila
1Department of Biosciences, Division of Animal Physiology
Mart Saarma
2Institute of Biotechnology, Viikki Biocenter, FIN-00014 University of Helsinki, Helsinki, Finland
Address correspondence to Claudio Rivera, Institute of Biotechnology and Division of Animal Physiology, Viiki Biocenter, PO Box 56, Viikinkaari 9, FIN-00014 University of Helsinki, Finland. Tel.: 358-9-191-59359. Fax: 358-9-191-59560. E-mail: [email protected]
*
Abbreviations used in this paper: BDNF, brain-derived neurotrophic factor; DG, dentate gyrus; EIPSP, reversal potential of IPSP; IPSP, inhibitory postsynaptic potential; NT-4, neurotrophin-4; TrkB-Fc, TrkB-soluble receptor body; Vm, membrane potential; Vrest, resting membrane potential.
Received:
September 03 2002
Revision Received:
October 31 2002
Accepted:
November 01 2002
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2002
J Cell Biol (2002) 159 (5): 747–752.
Article history
Received:
September 03 2002
Revision Received:
October 31 2002
Accepted:
November 01 2002
Citation
Claudio Rivera, Hong Li, Judith Thomas-Crusells, Hannele Lahtinen, Tero Viitanen, Avtandil Nanobashvili, Zaal Kokaia, Matti S. Airaksinen, Juha Voipio, Kai Kaila, Mart Saarma; BDNF-induced TrkB activation down-regulates the K+–Cl− cotransporter KCC2 and impairs neuronal Cl− extrusion . J Cell Biol 9 December 2002; 159 (5): 747–752. doi: https://doi.org/10.1083/jcb.200209011
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