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The Journal of Neuroscience, March 1, 2002, 22(5):1532-1540
Brain-Derived Neurotrophic Factor Induces Long-Term Potentiation
in Intact Adult Hippocampus: Requirement for ERK Activation Coupled to
CREB and Upregulation of Arc Synthesis
Shui-Wang
Ying1, *,
Marie
Futter2, *,
Kobi
Rosenblum2,
Mark J.
Webber3,
Stephen P.
Hunt3,
Timothy V. P.
Bliss2, and
Clive R.
Bramham1
1 Department of Physiology and Locus on Neuroscience,
University of Bergen, N-5009 Bergen, Norway,
2 Division of Neurophysiology, National Institute for
Medical Research, London NW7 1AA, United Kingdom, and
3 Department of Anatomy and Developmental Biology,
University College London, London WC1E 6BT, United Kingdom
Brain-derived neurotrophic factor (BDNF) is implicated in long-term
synaptic plasticity in the adult hippocampus, but the cellular
mechanisms are little understood. Here we used intrahippocampal microinfusion of BDNF to trigger long-term potentiation (BDNF-LTP) at
medial perforant path-granule cell synapses in vivo.
BDNF infusion led to rapid phosphorylation of the mitogen-activated
protein (MAP) kinases ERK (extracellular signal-regulated
protein kinase) and p38 but not JNK (c-Jun N-terminal protein
kinase). These effects were restricted to the infused dentate
gyrus; no changes were observed in microdissected CA3 and CA1 regions.
Local infusion of MEK (MAP kinase kinase) inhibitors (PD98059
and U0126) during BDNF delivery abolished BDNF-LTP and the associated
ERK activation. Application of MEK inhibitor during established
BDNF-LTP had no effect. Activation of MEK-ERK is therefore required for
the induction, but not the maintenance, of BDNF-LTP. BDNF-LTP was
further coupled to ERK-dependent phosphorylation of the transcription
factor cAMP response element-binding protein. Finally, we investigated
the expression of two immediate early genes, activity-regulated
cytoskeleton-associated protein (Arc) and Zif268, both
of which are required for generation of late, mRNA synthesis-dependent
LTP. BDNF infusion resulted in selective upregulation of mRNA and
protein for Arc. In situ hybridization
showed that Arc transcripts are rapidly and extensively delivered to granule cell dendrites. U0126 blocked Arc
upregulation in parallel with BDNF-LTP. The results support a model in
which BDNF triggers long-lasting synaptic strengthening through MEK-ERK and selective induction of the dendritic mRNA species
Arc.
Key words:
brain derived neurotrophic factor; BDNF; long-term
potentiation; LTP; extracellular signal-regulated protein kinase; ERK; mitogen-activated protein kinase; MAPK; activity-regulated
cytoskeleton-associated protein; Arc; synaptic
plasticity; hippocampus; dentate gyrus
*
S.W.Y. and M.F. contributed equally to this work.
Copyright © 2002 Society for Neuroscience 0270-6474/02/2251532-09$05.00/0
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