Neurobiology through the looking-glass: d-serine as a new glial-derived transmitter

Abstract

d-Amino acids have been known to be present in bacteria for more than 50 years, but only recently they were identified in mammals. The occurrence of d-amino acids in mammals challenge classic concepts in biology in which only l-amino acids would be present or thought to play important roles. Recent discoveries uncovered a role of endogenous d-serine as a putative glial-derived transmitter that regulates glutamatergic neurotransmission in mammalian brain. Free d-serine levels in the brain are about one third of l-serine values and its extracellular concentration is higher than many common l-amino acids. d-Serine occurs in protoplasmic astrocytes, a class of glial cells that ensheath the synapses and modulate neuronal activity. Biochemical and electrophysiological studies suggest that endogenous d-serine is a physiological modulator at the co-agonist site of NMDA-type of glutamate receptors. We previously showed that d-serine is synthesized by a glial serine racemase, a novel enzyme converting l- to d-serine in mammalian brain. The enzyme requires pyridoxal 5′-phosphate and it was the first racemase to be cloned from eucaryotes. Inhibitors of serine racemase have therapeutic implications for pathological processes in which over-stimulation of NMDA receptors takes place, such as stroke and neurodegenerative diseases. Here, we review the role of endogenous d-serine in modulating NMDA neurotransmission, its biosynthetic apparatus and the potential usefulness of serine racemase inhibitors as a novel neuroprotective strategy to decrease glutamate/NMDA excitotoxicity.