D-Serine is an endogenous ligand for NMDARs generated from L-serine by the enzyme serine racemase (Srr). Both neuronal and glial localizations have been reported for D-serine and Srr. 3-Phosphoglycerate dehydrogenase is an exclusively astrocytic enzyme that catalyzes the first committed step of L-serine biosynthesis. Using transgenic mice expressing enhanced green fluorescent protein under the Srr promoter and mice with targeted deletion of Srr or 3-Phosphoglycerate dehydrogenase, we demonstrate predominantly neuronal sources of D-serine dependent on astrocytic supply of L-serine. These findings clarify the cellular basis for the regulation of NMDAR neurotransmission by D-serine.
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