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The Journal of Neuroscience, January 1, 2003, 23(1):349-357
Activation of the TrkB Neurotrophin Receptor Is Induced by
Antidepressant Drugs and Is Required for Antidepressant-Induced
Behavioral Effects
Tommi
Saarelainen1, *,
Panu
Hendolin1, *,
Guilherme
Lucas4,
Eija
Koponen1,
Mikko
Sairanen1,
Ewen
MacDonald2,
Karin
Agerman4,
Annakaisa
Haapasalo1,
Hiroyuki
Nawa5,
Raquel
Aloyz6,
Patrik
Ernfors4, and
Eero
Castrén1, 3
1 Department of Neurobiology, A. I. Virtanen
Institute, Departments of 2 Pharmacology and Toxicology
and 3 Psychiatry, University of Kuopio, 70211 Kuopio,
Finland, 4 Department of Medical Biochemistry and
Biophysics, Karolinska Institute, 17177 Stockholm, Sweden,
5 Department of Molecular Biology, Neurobiology, Brain
Research Institute, Niigata University, Niigata 951-8585, Japan, and
6 Center for Neuronal Survival, Montreal Neurological
Institute, McGill University, Montreal, Quebec, Canada H3A 2B4
Recent studies have indicated that exogenously administered
neurotrophins produce antidepressant-like behavioral effects. We have
here investigated the role of endogenous brain-derived neurotrophic
factor (BDNF) and its receptor trkB in the mechanism of action
of antidepressant drugs. We found that trkB.T1-overexpressing transgenic mice, which show reduced trkB activation in brain, as well
as heterozygous BDNF null
(BDNF+/ ) mice, were resistant
to the effects of antidepressants in the forced swim test, indicating
that normal trkB signaling is required for the behavioral effects
typically produced by antidepressants. In contrast,
neurotrophin-3+/ mice showed a
normal behavioral response to antidepressants. Furthermore, acute as
well as chronic antidepressant treatment induced autophosphorylation
and activation of trkB in cerebral cortex, particularly in the
prefrontal and anterior cingulate cortex and hippocampus. Tyrosines in
the trkB autophosphorylation site were phosphorylated in response to
antidepressants, but phosphorylation of the shc binding site was
not observed. Nevertheless, phosphorylation of cAMP response
element-binding protein was increased by antidepressants in the
prefrontal cortex concomitantly with trkB phosphorylation and this
response was reduced in trkB.T1-overexpressing mice. Our
data suggest that antidepressants acutely increase trkB signaling in a
BDNF-dependent manner in cerebral cortex and that this signaling is
required for the behavioral effects typical of antidepressant drugs.
Neurotrophin signaling increased by antidepressants may induce
formation and stabilization of synaptic connectivity, which gradually
leads to the clinical antidepressive effects and mood recovery.
Key words:
TrkB; neurotrophin receptor; antidepressant; BDNF; CREB; cerebral cortex
*
T.S. and P.H. contributed equally to this work.
Copyright © 2003 Society for Neuroscience 0270-6474/03/231349-09$05.00/0
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