New insights into the regulation of D-serine and glycine in the central nervous system

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 (Phgdh) 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 Phgdh, 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. Slc7a10 (Asc-1) is a sodium-independent neutral amino acid transporter known to be the primary mediator of D-serine transport in the brain. Slc7a10 transports a number of additional amino acids including glycine, L-alanine, L-serine, and L-cysteine, as well as their D-enantiomers. We find that Slc7a10 is enriched in cerebellar Bergmann glia and within a subset of astrocytes of the caudal brain and spinal cord, in a distribution corresponding to high densities of glycinergic inhibitory synapses. Accordingly, we find that spontaneous glycinergic postsynaptic currents in motor neurons of mice lacking Slc7a10 show substantially diminished amplitude, identifying the likely etiology of sustained myoclonus and early postnatal lethality previously described for these animals. These observations establish a critical role for astrocytic Slc7a10 in glycinergic inhibitory function in the central nervous system