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.

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Keywords BDNF, disinhibition, dorsal horn, Fyn, GluN2B, KCC2, lamina I, NMDA receptor, pain, TrkB
Persistent URL
Journal Cell Reports
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