Molecular Determinants of D-serine-mediated Gliotransmission: from Release to Function

Since the late 80s, it is recognized that functional activation of N-methyl D-aspartate receptors (NMDARs) requires the binding of both glutamate and glycine. However, the surprising discovery that the wrong isomer of serine, D-serine, is present in mammals has profoundly challenged this dogmatic model of NMDARs activation. Indeed, there are accumulating evidence indicating that D-serine is the endogenous ligand for the glycine modulatory binding site in many brain areas. D-Serine is synthesized in glial cells by serine racemase (SR) and released upon activation of glutamate receptors. Here, we will provide an overview of recent findings on the molecular and cellular mechanisms involved in the synthesis and release of this gliotransmitter. We will also emphasize the function of this novel messenger in regulating synaptic excitatory transmission and plasticity in different brain areas. Because it fulfils all criteria for a gliotransmitter, D-serine regulatory action on glutamatergic transmission further illustrates the emerging concept of the "tripartite synapse".