title: Potentiation of Synaptic GluN2B NMDAR Currents by Fyn Kinase Is Gated through BDNF-Mediated Disinhibition in Spinal Pain Processing.
abstract: 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.
authors.affiliation: Program in Neurosciences & Mental Health, Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada. Electronic address: mike.hildebrand@carleton.ca.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Hildebrand
authors.affiliation: Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06519, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Dedek
authors.affiliation: Program in Neurosciences & Mental Health, Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A1, Canada.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Program in Neurosciences & Mental Health, Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada.
authors.forename: Ameet S
authors.initials: AS
authors.lastname: Sengar
authors.affiliation: Program in Neurosciences & Mental Health, Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A1, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Beggs
authors.affiliation: Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06519, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lombroso
authors.affiliation: Program in Neurosciences & Mental Health, Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A1, Canada. Electronic address: mike.salter@utoronto.ca.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Salter
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009437:Neuralgia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D059348:Peripheral Nerve Injuries / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D020813:Receptor, trkB / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism; D013127:Spinal Nerves / Q000378:metabolism / Q000503:physiopathology; D013569:Synapses / Q000235:genetics / Q000473:pathology; D019061:src-Family Kinases / Q000235:genetics
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D051076:Proto-Oncogene Proteins c-fyn; D020813:Receptor, trkB; D016194:Receptors, N-Methyl-D-Aspartate; D019061:src-Family Kinases; C121001:NR2B NMDA receptor; C000621230:Ntrk2 protein, rat; C494961:Fyn protein, rat
keywords: BDNF; Fyn; GluN2B; KCC2; NMDA receptor; TrkB; disinhibition; dorsal horn; lamina I; pain