Antagonistic effects of TrkB and p75NTR on NMDA receptor currents in post-synaptic densities transplanted into Xenopus oocytes

Mauricio Sandoval, Rodrigo Sandoval, Ulrich Thomas, Christina Spilker, Karl Heinz Smalla, Romina Falcon, Juan José Marengo, Rodrigo Calderón, Verónica Saavedra, Rolf Heumann, Francisca Bronfman, Craig C. Garner, Eckart D. Gundelfinger, Ursula Wyneken

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are essential regulators of synaptic function in the adult CNS. A TrkB-mediated effect at excitatory synapses is enhancement of NMDA receptor (NMDA-R)-mediated currents. Recently, opposing effects of TrkB and the pan-neurotrophin receptor p75NTR on long-term synaptic depression and long-term potentiation have been reported in the hippocampus. To further study the regulation of NMDA-Rs by neurotrophin receptors in their native protein environment, we micro-transplanted rat forebrain post-synaptic densities (PSDs) into Xenopus oocytes. One-minute incubations of oocytes with BDNF led to dual effects on NMDA-R currents: either TrkB-dependent potentiation or TrkB-independent inhibition were observed. Pro-nerve growth factor, a ligand for p75 NTR but not for TrkB, produced a reversible, dose-dependent, TrkB-independent and p75NTR-dependent inhibition of NMDA-Rs. Fractionation experiments showed that p75NTR is highly enriched in the PSD protein fraction. Immunoprecipitation and pull-down experiments further revealed that p75NTR is a core component of the PSD, where it interacts with the PDZ3 domain of the scaffolding protein SAP90/PSD-95. Our data provide striking evidence for a rapid inhibitory effect of p75NTR on NMDA-R currents that antagonizes TrkB-mediated NMDA-R potentiation. These opposing mechanisms might be present in a large proportion of forebrain synapses and may contribute importantly to synaptic plasticity.
Original languageAmerican English
Pages (from-to)1672-1684
Number of pages13
JournalJournal of Neurochemistry
Volume101
Issue number6
DOIs
StatePublished - 1 Jun 2007

Keywords

  • Brain-derived neurotrophic factor
  • Neurotrophins
  • NMDA receptor
  • Post-synaptic density
  • Synapse

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