Impaired NMDA receptor-mediated postsynaptic function and blunted NMDA receptor-dependent persistent pain in mice lacking postsynaptic density-93 protein

Yuan Xiang Tao, Gavin Rumbaugh, Guo Du Wang, Ronald S. Petralia, Chengshui Zhao, Frederick W. Kauer, Feng Tao, Min Zhuo, Robert J. Wenthold, Srinivasa N. Raja, Richard L. Huganir, David S. Bredt, Roger A. Johns

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6703-6712
Number of pages10
JournalJournal of Neuroscience
Volume23
Issue number17
DOIs
StatePublished - Jul 30 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Keywords

  • Forebrain
  • NMDA receptors
  • PSD-93
  • Persistent pain
  • Signal cord
  • Surface expression

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