Antagonistic effects of TrkB and p75^NTR on NMDA receptor currents in post‐synaptic densities transplanted into Xenopus oocytes

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 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 Neurotrophins, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), bind to two structurally unrelated receptors, Trk receptor tyrosine kinases and the p75 NTR receptor. NGF and BDNF act selectively on TrkA and TrkB, respectively, triggering well characterized intracellular cascades, but also acting directly on ionic channels on a rapid time scale (Huang and Reichardt 2003 These authors contributed equally to this work.Abbreviations used: BDNF, brain-derived neurotrophic factor; LTP, long-term potentiation; NGF, nerve growth factor; PSD, post-synaptic density; MBP, maltose-binding protein.

Homeostatic NMDA receptor down‐regulation via brain derived neurotrophic factor and nitric oxide‐dependent signalling in cortical but not in hippocampal neurons

“…As shown previously, the net effect of BDNF in forebrain PSDs resulted from interaction with different receptors, leading to TrkB‐dependent potentiation and/or p75 NTR ‐dependent inhibition (Sandoval et al. 2007).…”

“…To test the functional effect of BDNF‐dependent NO production on NMDA‐R currents in isolated PSDs, we incorporated them into the cell membrane of Xenopus laevis oocytes (Sandoval et al. 2007; Eusebi et al.…”

“…We used the method described previously to measure NMDA‐activated ion currents present in PSDs transplanted into the Xenopus laevis oocyte plasma membrane (Sandoval et al. 2007; Eusebi et al.…”

Small Molecule, Non-Peptide p75NTR Ligands Inhibit Aβ-Induced Neurodegeneration and Synaptic Impairment

“…Recent findings suggest that p75 NTR is highly enriched in post-synaptic densities and interacts with the PDZ3 domain of the PSD-95 scaffolding protein [39]. In addition, evidence continues to accumulate that Aβ might impair synaptic function by perturbing PSD-95 related structures and function [40], [41].…”

Selective Upregulation of Brain-Derived Neurotrophic Factor (BDNF) Transcripts and BDNF Direct Induction of Activity Independent N-Methyl-D-Aspartate Currents in Temporal Lobe Epilepsy Patients with Hippocampal Sclerosis

“…44 BDNF has been found to increase the NMDA receptor-gated Ca 2+ influx into dendrites of neurons with Ca 2+ oscillations by confocal laser microscopy in rats. 45 Activation of TrkB receptors of BDNF potentiated NMDA 46 Moreover, BDNF has been found to increase NMDA receptor single channel open probability, resulting in enhancement of synaptic transmission in cultures of hippocampi. 25 Brain-derived neurotrophic factor has been implicated in sprouting in TLE, and the resulting increase in NMDA glutamate receptors appears to mediate increased recurrent activation.…”