D-Serine

Proc Natl Acad Sci U S A,2000 Apr 25;97(9):4926-31.

D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor.[Pubmed: 10781100]

Functional activity of N-methyl-D-aspartate (NMDA) receptors requires both glutamate binding and the binding of an endogenous coagonist that has been presumed to be glycine, although D-Serine is a more potent agonist. Localizations of D-Serine and it biosynthetic enzyme serine racemase approximate the distribution of NMDA receptors more closely than glycine.
METHODS AND RESULTS:
We now show that selective degradation of D-Serine with D-amino acid oxidase greatly attenuates NMDA receptor-mediated neurotransmission as assessed by using whole-cell patch-clamp recordings or indirectly by using biochemical assays of the sequelae of NMDA receptor-mediated calcium flux. The inhibitory effects of the enzyme are fully reversed by exogenously applied D-Serine, which by itself did not potentiate NMDA receptor-mediated synaptic responses.
CONCLUSIONS:
Thus, D-Serine is an endogenous modulator of the glycine site of NMDA receptors and fully occupies this site at some functional synapses.

Proc Natl Acad Sci U S A,1995 Apr 25;92(9):3948-52.

D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release.[Pubmed: 7732010]

METHODS AND RESULTS:
Using an antibody highly specific for D-Serine conjugated to glutaraldehyde, we have localized endogenous D-Serine in rat brain. Highest levels of D-Serine immunoreactivity occur in the gray matter of the cerebral cortex, hippocampus, anterior olfactory nucleus, olfactory tubercle, and amygdala. Localizations of D-Serine immunoreactivity correlate closely with those of D-Serine binding to the glycine modulatory site of the N-methyl-D-aspartate (NMDA) receptor as visualized by autoradiography and are inversely correlated to the presence of D-amino acid oxidase. D-Serine is enriched in process-bearing glial cells in neuropil with the morphology of protoplasmic astrocytes. In glial cultures of rat cerebral cortex, D-Serine is enriched in type 2 astrocytes.
CONCLUSIONS:
The release of D-Serine from these cultures is stimulated by agonists of non-NMDA glutamate receptors, suggesting a mechanism by which astrocyte-derived D-Serine could modulate neurotransmission. D-Serine appears to be the endogenous ligand for the glycine site of NMDA receptors.

Neuropsychopharmacology, 2008, 33(5):1004-1018.

D-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning.[Pubmed: 17625504]

The contributions of hippocampal long-term depression (LTD) to explicit learning and memory are poorly understood. Electrophysiological and behavioral studies examined the effects of modulating NMDA receptor-dependent LTD on spatial learning in the Morris water maze (MWM).
METHODS AND RESULTS:
The NMDA receptor co-agonist D-Serine substantially enhanced NR2B-dependent LTD, but not long-term potentiation (LTP) or depotentiation, in hippocampal slices from adult wild type mice. Exogenous D-Serine did not alter MWM acquisition, but substantially enhanced subsequent reversal learning of a novel target location and performance in a delayed-matching-to-place task. Conversely, an NR2B antagonist disrupted reversal learning and promoted perseveration. Endogenous synaptic D-Serine likely saturates during LTP induction because exogenous D-Serine rescued deficient LTP and MWM acquisition in Grin1(D481N) mutant mice having a lower D-Serine affinity.
CONCLUSIONS:
Thus, D-Serine may enhance a form of hippocampal NR2B-dependent LTD that contributes to spatial reversal learning. By enhancing this form of synaptic plasticity, D-Serine could improve cognitive flexibility in psychiatric disorders characterized by perseveration of aberrant ideation or behaviors.

Neurosci Lett,2005 Apr 29;379(1):7-12.

D-serine enhances impaired long-term potentiation in CA1 subfield of hippocampal slices from aged senescence-accelerated mouse prone/8.[Pubmed: 15814189]

The molecular and cellular mechanisms underlying the cognitive deficiency of senescence-accelerated mouse prone/8 (SAMP8) have been attributed to many pathological changes in neurons. Recently, increasing evidence has shown that astrocytes, by mean of D-Serine, involve in the process of synaptic transmission.
METHODS AND RESULTS:
Here we reported that the long-term potentiation (LTP) in CA1 area of hippocampal slices prepared from 2-, 6- and 12-month-old SAMP8 significantly decreased with age. Meanwhile, the LTP in the slices of 6- and 12-month-old mice markedly decreased below that of the age-matched normal strain SAMR1. Supplement with exogenous D-Serine, a main product of astrocytes and a coagonist at the "glycin-binding" site of N-methyl-d-aspartate (NMDA) receptors, not only directly enhanced the deficient LTP but also rescued the abolished LTP by d-amino acid oxidase (DAAO) in slices from 12-month-old SAMP8. This ameliorative effect of D-Serine was inhibited by either AP-V or 5,7-dichlorokynurenic acid (DCKA).
CONCLUSIONS:
These results suggest that absence of D-Serine or dysfunction of the astrocytes possibly was one of mechanisms underlying the decrease of NMDA receptor-dependent LTP and cognition in aged SAMP8.