The Rise and Fall of the d-Serine-Mediated Gliotransmission Hypothesis

d-Serine modulates N-methyl d-aspartate receptors (NMDARs) and regulates synaptic plasticity, neurodevelopment, and learning and memory. However, the primary site of d-serine synthesis and release remains controversial, with some arguing that it is a gliotransmitter and others defining it as a neuronal cotransmitter. Results from several laboratories using different strategies now show that the biosynthetic enzyme of d-serine, serine racemase (SR), is expressed almost entirely by neurons, with few astrocytes appearing to contain d-serine. Cell-selective suppression of SR expression demonstrates that neuronal, rather than astrocytic d-serine, modulates synaptic plasticity. Here, we propose an alternative conceptualization whereby astrocytes affect d-serine levels by synthesizing l-serine that shuttles to neurons to fuel the neuronal synthesis of d-serine.