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The Journal of Neuroscience, July 30, 2003, 23(17):6703-6712

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Impaired NMDA Receptor-Mediated Postsynaptic Function and Blunted NMDA Receptor-Dependent Persistent Pain in Mice Lacking Postsynaptic Density-93 Protein

Yuan-Xiang Tao,^1 * Gavin Rumbaugh,^2 * Guo-Du Wang,^3 * Ronald S. Petralia,⁴ Chengshui Zhao,¹ Frederick W. Kauer,⁵ Feng Tao,¹ Min Zhuo,³ Robert J. Wenthold,⁴ Srinivasa N. Raja,¹ Richard L. Huganir,² David S. Bredt,⁵ and Roger A. Johns¹

¹Department of Anesthesiology and Critical Care Medicine and ²Howard Hughes Medical Institute, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, ³Washington University Pain Center, Departments of Anesthesiology, Anatomy and Neurobiology, and Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, ⁴Laboratory of Neurochemistry, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892, and ⁵Department of Physiology, University of California San Francisco, San Francisco, California 94143-0444

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.

Key words: PSD-93; NMDA receptors; surface expression; persistent pain; spinal cord, forebrain

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Received Mar. 4, 2003; revised Jun. 4, 2003; accepted Jun. 10, 2003.

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