The serine shuttle between glia and neurons: Implications for neurotransmission and neurodegeneration

d-Serine is a physiological co-agonist of NMDARs (N-methyl-d-aspartate receptors) required for neurotransmission, synaptic plasticity and neurotoxicity. There is no consensus, however, on the relative roles of neurons and astrocytes in d-serine signalling. The effects of d-serine had been attributed to its role as a gliotransmitter specifically produced and released by astrocytes. In contrast, recent studies indicate that neurons regulate their own NMDARs by releasing d-serine via plasma membrane transporters and depolarization-sensitive pathways. Only a minority of astrocytes contain authentic d-serine, whereas neuronal d-serine accounts for up to 90% of the total d-serine pool. Neuronal and glial d-serine production requires astrocytic l-serine generated by a 3-phosphoglycerate dehydrogenase-dependent pathway. These findings support a model whereby astrocyte-derived l-serine shuttles to neurons to fuel the synthesis of d-serine by serine racemase. We incorporate these new findings in a revised model of serine dynamics, called the glia-neuron serine shuttle, which highlights the role of glia-neuron cross-talk for optimal NMDAR activity and brain development.