l-Serine links metabolism with neurotransmission

•l-serine is mostly synthetized by glial cells in the brain.•l-Serine is a metabolic hub.•l-Serine links glial metabolism with synaptic activity and plasticity.•A lack of l-serine synthesis may contribute to many brain disorders. Brain energy metabolism is often considered as a succession of biochemical steps that metabolize the fuel (glucose and oxygen) for the unique purpose of providing sufficient ATP to maintain the huge information processing power of the brain. However, a significant fraction (10–15 %) of glucose is shunted away from the ATP-producing pathway (oxidative phosphorylation) and may be used to support other functions. Recent studies have pointed to the marked compartmentation of energy metabolic pathways between neurons and glial cells. Here, we focused our attention on the biosynthesis of l-serine, a non-essential amino acid that is formed exclusively in glial cells (mostly astrocytes) by re-routing the metabolic fate of the glycolytic intermediate, 3-phosphoglycerate (3PG). This metabolic pathway is called the phosphorylated pathway and transforms 3PG into l-serine via three enzymatic reactions. We first compiled the available data on the mechanisms that regulate the flux through this metabolic pathway. We then reviewed the current evidence that is beginning to unravel the roles of l-serine both in the healthy and diseased brain, leading to the notion that this specific metabolic pathway connects glial metabolism with synaptic activity and plasticity. We finally suggest that restoring astrocyte-mediated l-serine homeostasis may provide new therapeutic strategies for brain disorders.