Potentiation of Synaptic GluN2B NMDAR Currents by Fyn Kinase Is Gated through BDNF-Mediated Disinhibition in Spinal Pain Processing

Cell Rep. 2016 Dec 6;17(10):2753-2765. doi: 10.1016/j.celrep.2016.11.024.


In chronic pain states, the neurotrophin brain-derived neurotrophic factor (BDNF) transforms the output of lamina I spinal neurons by decreasing synaptic inhibition. Pain hypersensitivity also depends on N-methyl-D-aspartate receptors (NMDARs) and Src-family kinases, but the locus of NMDAR dysregulation remains unknown. Here, we show that NMDAR-mediated currents at lamina I synapses are potentiated in a peripheral nerve injury model of neuropathic pain. We find that BDNF mediates NMDAR potentiation through activation of TrkB and phosphorylation of the GluN2B subunit by the Src-family kinase Fyn. Surprisingly, we find that Cl--dependent disinhibition is necessary and sufficient to prime potentiation of synaptic NMDARs by BDNF. Thus, we propose that spinal pain amplification is mediated by a feedforward mechanism whereby loss of inhibition gates the increase in synaptic excitation within individual lamina I neurons. Given that neither disinhibition alone nor BDNF-TrkB signaling is sufficient to potentiate NMDARs, we have discovered a form of molecular coincidence detection in lamina I neurons.

Keywords: BDNF; Fyn; GluN2B; KCC2; NMDA receptor; TrkB; disinhibition; dorsal horn; lamina I; pain.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / genetics*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Humans
  • Neuralgia / genetics*
  • Neuralgia / metabolism
  • Neuralgia / physiopathology
  • Neurons / metabolism
  • Neurons / pathology
  • Peripheral Nerve Injuries / genetics
  • Peripheral Nerve Injuries / metabolism*
  • Peripheral Nerve Injuries / physiopathology
  • Proto-Oncogene Proteins c-fyn / genetics*
  • Proto-Oncogene Proteins c-fyn / metabolism
  • Rats
  • Receptor, trkB / genetics*
  • Receptors, N-Methyl-D-Aspartate / genetics*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Spinal Nerves / metabolism
  • Spinal Nerves / physiopathology
  • Synapses / genetics
  • Synapses / pathology
  • src-Family Kinases / genetics


  • Brain-Derived Neurotrophic Factor
  • NMDA receptor A1
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Ntrk2 protein, rat
  • Receptor, trkB
  • Fyn protein, rat
  • Proto-Oncogene Proteins c-fyn
  • src-Family Kinases

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