D-amino acids are prominent in bacteria, and there have been occasional reports of D-amino acids in invertebrates (1, 2), whereas animal tissues were believed to contain L-amino acids exclusively. Recently, however, D-serine (3–6) and D-aspartate (7, 8) were reported in mammalian tissues, especially in the nervous system. Utilizing highly selective antibodies, we localized D-aspartate to neuroendocrine tissues (9), while the immunohistochemical localizations of D-serine closely resemble N-methyl-D-aspartate (NMDA) receptors for the neurotransmitter glutamate, consistent with chemical measurements of the distribution of D-serine (10, 11).
Glutamate cannot activate the NMDA receptor in the absence of added glycine, which indicates a “glycine site” for the receptor (12, 13). D-Serine is up to three times more potent than glycine at this site (14), suggesting that D-serine is the endogenous ligand for this site. D-Serine is localized exclusively to Type II astrocytes, a form of glia concentrated in gray matter in the same areas of the brain as NMDA receptors (10). Stimulation of the kainate subtype of glutamate receptors releases D-serine from Type II astrocytes, which implies that synaptic release of glutamate triggers release of D-serine from the astrocytes to activate NMDA receptors physiologically (10). While in most parts of the brain the distribution of D-serine resembles NMDA receptors far better than does the distribution of glycine, in some areas glycine and NMDA receptors are co-localized, suggesting that D-serine is the predominant ligand for the receptor in most brain areas but that glycine serves this purpose in some sites (11).
Activation of NMDA receptors is an important pathologic event in stroke and several neurodegenerative diseases, leading to cell death. Decreased activation of NMDA receptors can thus have a beneficial effect in the treatment of any condition or disease that includes acute or chronic neuronal death or dysfunction mediated by overactivation of NMDA receptors. Overactivation of NMDA receptors is involved in stroke, epilepsy, and chronic neurodegenerative diseases such as Parkinson's disease, Huntington's disease, motor neuron diseases, and Alzheimer's disease. Thus, there is a need in the art to determine how D-serine is formed in the brain, so that its concentration in NMDA-related diseases can be regulated.