BDNF-induced TrkB activation down-regulates the K+-Cl- cotransporter KCC2 and impairs neuronal Cl- extrusion.
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.
Rivera
Claudio
C
Department of Biosciences, Division of Animal Physiology, Institute of Biotechnology, University of Helsinki, Finland. rivera@operoni.helsinki.fi
Li
Hong
H
Thomas-Crusells
Judith
J
Lahtinen
Hannele
H
Viitanen
Tero
T
Nanobashvili
Avtandil
A
Kokaia
Zaal
Z
Airaksinen
Matti S
MS
Voipio
Juha
J
Kaila
Kai
K
Saarma
Mart
M
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002712:Chlorides / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D017136:Ion Transport; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D027981:Symporters / Q000378:metabolism*; D013997:Time Factors; D000096922:K Cl- Cotransporters
D019208:Brain-Derived Neurotrophic Factor; D002712:Chlorides; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D020813:Receptor, trkB; D011994:Recombinant Proteins; D027981:Symporters; D000096922:K Cl- Cotransporters; C073922:neurotrophin 4