title: GluN2B and GluN2D NMDARs dominate synaptic responses in the adult spinal cord.
abstract: The composition of the postsynaptic ionotropic receptors that receive presynaptically released transmitter is critical not only for transducing and integrating electrical signals but also for coordinating downstream biochemical signaling pathways. At glutamatergic synapses in the adult CNS an overwhelming body of evidence indicates that the NMDA receptor (NMDAR) component of synaptic responses is dominated by NMDARs containing the GluN2A subunit, while NMDARs containing GluN2B, GluN2C, or GluN2D play minor roles in synaptic transmission. Here, we discovered NMDAR-mediated synaptic responses with characteristics not described elsewhere in the adult CNS. We found that GluN2A-containing receptors contribute little to synaptic NMDAR responses while GluN2B dominates at synapses of lamina I neurons in the adult spinal cord. In addition, we provide evidence for a GluN2D-mediated synaptic NMDAR component in adult lamina I neurons. Strikingly, the charge transfer mediated by GluN2D far exceeds that of GluN2A and is comparable to that of GluN2B. Lamina I forms a distinct output pathway from the spinal pain processing network to the pain networks in the brain. The GluN2D-mediated synaptic responses we have discovered in lamina I neurons provide the molecular underpinning for slow, prolonged and feedforward amplification that is a fundamental characteristic of pain.
authors: 1] Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, ON, Canada [2] Department of Physiology, University of Toronto, Toronto, ON, Canada [3].
authors: Michael E
authors: ME
authors: Hildebrand
authors: 1] Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, ON, Canada [2] Department of Physiology, University of Toronto, Toronto, ON, Canada.
authors: Graham M
authors: GM
authors: Pitcher
authors: 1] Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, ON, Canada [2] Department of Physiology, University of Toronto, Toronto, ON, Canada.
authors: Erika K
authors: EK
authors: Harding
authors: 1] Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, ON, Canada [2] Department of Physiology, University of Toronto, Toronto, ON, Canada.
authors: Hongbin
authors: H
authors: Li
authors: 1] Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, ON, Canada [2] Department of Physiology, University of Toronto, Toronto, ON, Canada.
authors: Simon
authors: S
authors: Beggs
authors: 1] Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, ON, Canada [2] Department of Physiology, University of Toronto, Toronto, ON, Canada.
authors: Michael W
authors: MW
authors: Salter
mesh_terms: D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D018408:Patch-Clamp Techniques; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D006834:Hydrazines; D000096926:Benzenesulfonamides
chemical_list: D010636:Phenols; D010880:Piperidines; D011720:Pyrazoles; D015363:Quinolones; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013449:Sulfonamides; C568654:4-(5-(4-bromophenyl)-3-(6-methyl-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid; C121001:NR2B NMDA receptor; C464436:NR2D NMDA receptor; C109643:Ro 25-6981; C574512:TCN 201; D006834:Hydrazines; D000096926:Benzenesulfonamides