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The Journal of Neuroscience, December 31, 2008, 28(53):14486-14491; doi:10.1523/JNEUROSCI.5034-08.2008

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Brief Communications
NMDA- and β-Amyloid_1–42-Induced Neurotoxicity Is Attenuated in Serine Racemase Knock-Out Mice

Ran Inoue,¹ Kenji Hashimoto,² Tomomi Harai,¹ and Hisashi Mori¹

¹Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan, and ²Division of Clinical Neuroscience, Center for Forensic Mental Health, Chiba University, Chiba 260-8670, Japan

Correspondence should be addressed to Dr. Hisashi Mori, Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan. Email: hmori{at}med.u-toyama.ac.jp

D-Serine is detected in the brain and acts as a coagonist at the "glycine-site" of the NMDA-type glutamate receptor. Although D-serine can be directly produced from L-serine by serine racemase (SR), the relative contribution of SR in D-serine formation in vivo is not known. Pathological roles of brain D-serine mediating NMDA receptor overactivation are suggested in studies using in vitro culture systems. However, we have recently demonstrated the differential SR protein expression in vivo and in culture. Here, we reported an 90% decrease in forebrain D-serine content in SR knock-out (KO) mice. We also found a reduced neurotoxicity induced by NMDA- and Aβ_1–42- peptide injections into the forebrain in SR KO mice. These results suggest that SR is the major enzyme for D-serine production in the brain, D-serine is the predominant endogenous coagonist of the NMDA receptor in the forebrain, and D-serine may be involved in controlling the extent of NMDA receptor-mediated neurotoxic insults observed in disorders including Alzheimer's disease. The control of SR activity and D-serine level in the brain may lead to a novel strategy for neuroprotection against various neurodegenerative diseases.

Key words: D-Serine; serine racemase; NMDA receptor; neurotoxicity; Alzheimer's disease; gene knock-out mice

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Received Oct. 17, 2008; revised Nov. 21, 2008; accepted Nov. 25, 2008.

Correspondence should be addressed to Dr. Hisashi Mori, Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan. Email: hmori{at}med.u-toyama.ac.jp

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