Physiological relevance of endogenous free D-serine in the mammalian brain: are scientists on a royal road for the treatment of glutamatergic-related brain disorders?

Over the last century, it has been considered that amino acids in mammalian tissues and body fluids occur solely in the L-configuration whether free or as components of peptides and proteins. However, the recent discovery that high levels of D-serine and D-aspartate are present in Mammals overturns this long-cherished theory. In this review, we focus on recent findings regarding the physiological relevance of D-serine, a new neurotransmitter formed in glial cells, that serves as the endogenous ligand for the accessory strychnine-insensitive glycine site of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. This unusual molecule not only questions our basic ideas about how nerve cells converse but also offers a novel way to treat some brain disorders as both over-stimulation and down regulation of NMDA receptors has been implicated in a large number of acute and chronic degenerative conditions.