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.

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