Gliotransmission at central glutamatergic synapses: d-serine on stage

Long ignored and only considered as housekeeping cells for neurons, astroglial cells in the last decade have gained increasing attention as key players of higher functions in healthy brain, but also in diseases. This revolution in our way to think the active brain culminates in the concept of a tripartite synapse, which considers glial cells and notably astrocytes as an integral dynamic partner of synapses. Glia not only listens but also talks to neurons through the release of neuroactive substances. Recently much attention has been paid to the role played by the atypical amino acid d-serine in this signalling pathway. This molecule synthesized through racemization of l-serine fulfils most criteria as a gliotransmitter and as the endogenous ligand for the strychnine-insensitive glycine binding site of the NMDA receptors. d-Serine is considered to be a permissive factor for long-term changes in synaptic plasticity and neuronal migration through activation of NMDA receptors. It is also known that disturbance of NMDA receptors activity can cause cell death. Not surprisingly, then, d-serine has also been found to promote neurons death in experimental models of β-amyloid peptide-induced neuroinflammation and of ischaemia by overactivating the NMDA receptors. Finally, in a more recent past, studies have pointed to the molecular mechanisms leading to d-serine release into and removal from the synaptic cleft.