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.

Additional Metadata
Keywords BDNF, disinhibition, dorsal horn, Fyn, GluN2B, KCC2, lamina I, NMDA receptor, pain, TrkB
Persistent URL dx.doi.org/10.1016/j.celrep.2016.11.024
Journal Cell Reports
Citation
Hildebrand, M, Xu, J. (Jian), Dedek, A. (Annemarie), Li, Y. (Yi), Sengar, A.S. (Ameet S.), Beggs, S. (Simon), … Salter, M.W. (Michael W.). (2016). Potentiation of Synaptic GluN2B NMDAR Currents by Fyn Kinase Is Gated through BDNF-Mediated Disinhibition in Spinal Pain Processing. Cell Reports, 17(10), 2753–2765. doi:10.1016/j.celrep.2016.11.024