Impaired NMDA receptor-mediated postsynaptic function and blunted NMDA receptor-dependent persistent pain in mice lacking postsynaptic density-93 protein.
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.
Tao
Yuan-Xiang
YX
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. ytau@jhmi.edu
Rumbaugh
Gavin
G
Wang
Guo-Du
GD
Petralia
Ronald S
RS
Zhao
Chengshui
C
Kauer
Frederick W
FW
Tao
Feng
F
Zhuo
Min
M
Wenthold
Robert J
RJ
Raja
Srinivasa N
SN
Huganir
Richard L
RL
Bredt
David S
DS
Johns
Roger A
RA
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*
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