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 Ying, Marie Futter, Kobi Rosenblum, Mark J. Webber, Stephen P. Hunt, Timothy V.P. Bliss, Clive R. Bramham

Research output: Contribution to journalArticlepeer-review

Abstract

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-LTR 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 LTR 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.

Original languageEnglish
Pages (from-to)1532-1540
Number of pages9
JournalJournal of Neuroscience
Volume22
Issue number5
DOIs
StatePublished - 1 Mar 2002
Externally publishedYes

Keywords

  • Activity-regulated cytoskeleton-associated protein
  • Arc
  • BDNF
  • Brain derived neurotrophic factor
  • ERK
  • Extracellular signal-regulated protein kinase
  • LTP
  • Long-term potentiation
  • MAPK
  • Mitogen-activated protein kinase
  • Synaptic plasticity

ASJC Scopus subject areas

  • General Neuroscience

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