NMDA- and β-Amyloid1-42-Induced Neurotoxicity Is Attenuated in Serine Racemase Knock-Out Mice

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 similar to 90% decrease in forebrain D-serine content in SR knock-out (KO) mice. We also found a reduced neurotoxicity induced by NMDA- and A beta(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.