Novel neuroglial and glioglial relationships mediated by L-serine metabolism

L-Serine is a non-essential amino acid that can be synthesized in the body. It derives from an intermediate of the glycolytic pathway, 3-phosphoglycerate, and utilized for the syntheses of proteins, other amino acids, membrane lipids, heme, and nucleotides. Emerging evidence indicates that L-serine functions as a glia-derived trophic factor, which strongly promotes the survival and differentiation of cultured neurons. L-Serine biosynthetic enzyme 3-phosphoglycerate dehydrogenase (3PGDH) and small neutral amino acid transporter ASCT1 have been revealed to be expressed preferentially in the radial glia-astrocyte lineage and olfactory ensheathing glia of both adult and developing rodent brains. In contrast, these biosynthetic and transporter molecules for L-serine are faint or undetectable in neurons and phagocytic cells. In this review, we summarize recent progress to propose that L-serine synthesis in these glial cells and its supply to nearby neurons and other glia constitute a novel metabolic unit in the brain. Based on these neuroglial and glioglial relationships, glucose in neurons and phogocytes can be strategically used for energy production, while a variety of L-serine-derived biomolecules required for their proliferaton, survival, differentiation, and function are synthesized in and supplied from the radial glia-astrocyte lineage and olfactory ensheathing glia. A transient capillary expression of ASCT1 in fetal and neonatal brains further suggests that, in addition to the glia-borne L-serine, an active transport of blood-borne L-serine would play an essential role in neural development.