d-Serine Regulates Proliferation and Neuronal Differentiation of Neural Stem Cells from Postnatal Mouse Forebrain

Background and purpose: d-Serine, the endogenous co-agonist of N-methyl-d-aspartate (NMdA) receptors, has been recognized as an important gliotransmitter in the mammalian brain. d-serine has been shown to prevent psychostimulant-induced decrease in hippocampal neurogenesis. However, the mechanism whereby d-serine regulates neurogenesis has not been fully characterized. Therefore, this study was designed to investigate the impacts of d-serine on the proliferation, migration, and differentiation of primary cultured neural stem cells (NSCs). Methods and results: Immunohistochemistry analysis revealed NSCs expressed d-serine as well as serine racemase (SR). Degradation of endogenous d-serine with d-amino acid oxidase (dAAO) significantly inhibited the proliferation and neuronal differentiation of NSCs, but failed to affect their radial migration. Reversely, addition of exogenous d-serine did not affect the proliferation and migration of NSCs, but promoted NSC differentiation into neurons. Furthermore, dAAO could suppress the amplitude of glutamate-induced Ca2+ transient, and thereby, inhibited the phosphorylation of glycogen synthase kinase3 beta (GSK3 beta), extracellular signal-regulated kinases1/2 (ERK1/2), and cAMP-responsive element-binding protein (CREB). Conclusions: Our findings demonstrate for the first time that NSCs can synthesize d-serine and, thereby, promote themselves proliferation and neuronal differentiation, which may afford a novel therapeutic strategy for the neurological disorders that require nerve cell replenishment, such as neurodegenerative diseases and stroke.