D ‐Serine as a glial modulator of nerve cells

Until the last decade, it was widely accepted that D ‐amino acids had no functional role in higher organisms, but that they were restricted to lower organisms, such as bacteria, where they are integrated into the proteoglycans of the cell wall. However, D ‐serine proved to be an effective coagonist at the “glycine‐binding” site of the N‐methyl‐ D ‐aspartate (NMDA) glutamate receptors, and this observation led to chemical analyses that have now revealed the presence of high levels of D ‐serine in the central nervous system, including many regions of the brain and retina. D ‐Serine has been localized to astrocytes and can be released by glutamate through stimulation of AMPA receptors. A new enzyme, serine racemase has been localized to glial cells and converts L ‐serine to D ‐serine. Degradation of D ‐serine takes place through D ‐amino acid oxidase, an enzyme once thought to metabolize D ‐amino acids from external sources. Although the “glycine‐binding” site of NMDA receptors was initially regarded as a saturated site, evidence in many brain regions has established that this site is not saturated and is therefore modulated by interactions between glial cells and neurons. In some, but not all, studies, D ‐serine enhances NMDA‐mediated currents; a light‐evoked enhancement to NMDA currents has been reported in the retina. D ‐serine also plays a role in synaptic and cellular development, particularly in the cerebellum, where the normal developmental sequences underlying synapse formation onto Purkinje cells and the migration of granule cells are dependent on NMDA receptors during a time when high levels of D ‐serine are expressed in the Bergmann glia and other cerebellar astrocytes. D ‐serine must be added to the list of agents through which glial cells participate in controlling the excitability of neurons. © 2004 Wiley‐Liss, Inc.