Antagonistic effects of TrkB and p75(NTR) on NMDA receptor currents in post-synaptic densities transplanted into Xenopus oocytes.
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 p75(NTR) 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 p75(NTR)-dependent inhibition of NMDA-Rs. Fractionation experiments showed that p75(NTR) is highly enriched in the PSD protein fraction. Immunoprecipitation and pull-down experiments further revealed that p75(NTR) 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 p75(NTR) 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.
Sandoval
Mauricio
M
Laboratorio de Neurociencias, Universidad de Los Andes, Santiago, Chile.
Sandoval
Rodrigo
R
Thomas
Ulrich
U
Spilker
Christina
C
Smalla
Karl-Heinz
KH
Falcon
Romina
R
Marengo
Juan José
JJ
Calderón
Rodrigo
R
Saavedra
Verónica
V
Heumann
Rolf
R
Bronfman
Francisca
F
Garner
Craig C
CC
Gundelfinger
Eckart D
ED
Wyneken
Ursula
U
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D005260:Female; D047468:Immunoprecipitation; D009473:Neuronal Plasticity / Q000502:physiology; D009865:Oocytes / Q000502:physiology; D011498:Protein Precursors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000502:physiology*; D020813:Receptor, trkB / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D017981:Receptors, Neurotransmitter / Q000502:physiology*; D013570:Synaptic Membranes / Q000637:transplantation; D014982:Xenopus laevis
D019208:Brain-Derived Neurotrophic Factor; D011498:Protein Precursors; D020800:Receptor, Nerve Growth Factor; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D020813:Receptor, trkB