title: Impaired NMDA receptor-mediated postsynaptic function and blunted NMDA receptor-dependent persistent pain in mice lacking postsynaptic density-93 protein.
abstract: Modification of synaptic NMDA receptor (NMDAR) expression influences NMDAR-mediated synaptic function and associated persistent pain. NMDARs directly bind to a family of membrane-associated guanylate kinases (MAGUKs) that regulate surface and synaptic NMDAR trafficking in the CNS. We report here that postsynaptic density-93 protein (PSD-93), a postsynaptic neuronal MAGUK, is expressed abundantly in spinal dorsal horn and forebrain, where it colocalizes and interacts with NMDAR subunits NR2A and NR2B. Targeted disruption of the PSD-93 gene reduces not only surface NR2A and NR2B expression but also NMDAR-mediated excitatory postsynaptic currents and potentials, without affecting surface AMPA receptor expression or its synaptic function, in the regions mentioned above. Furthermore, mice lacking PSD-93 exhibit blunted NMDAR-dependent persistent pain induced by peripheral nerve injury or injection of Complete Freund's Adjuvant, although they display intact nociceptive responsiveness to acute pain. PSD-93 appears to be important for NMDAR synaptic targeting and function and to be a potential biochemical target for the treatment of persistent pain.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. ytau@jhmi.edu
authors.forename: Yuan-Xiang
authors.initials: YX
authors.lastname: Tao
authors.forename: Gavin
authors.initials: G
authors.lastname: Rumbaugh
authors.forename: Guo-Du
authors.initials: GD
authors.lastname: Wang
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Petralia
authors.forename: Chengshui
authors.initials: C
authors.lastname: Zhao
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Kauer
authors.forename: Feng
authors.initials: F
authors.lastname: Tao
authors.forename: Min
authors.initials: M
authors.lastname: Zhuo
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wenthold
authors.forename: Srinivasa N
authors.initials: SN
authors.lastname: Raja
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
authors.forename: David S
authors.initials: DS
authors.lastname: Bredt
authors.forename: Roger A
authors.initials: RA
authors.lastname: Johns
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D005620:Freund's Adjuvant; D051528:Guanylate Kinases; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D010146:Pain / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D010147:Pain Measurement; D018408:Patch-Clamp Techniques; D020671:Posterior Horn Cells / Q000166:cytology / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C033652:postsynaptic density proteins; D005620:Freund's Adjuvant; C501445:Dlg2 protein, mouse; D051528:Guanylate Kinases