Transport systems of serine at the brain barriers and in brain parenchymal cells

d-Serine is a co-agonist for NMDA-type glutamate receptors. Although d-serine levels in CSF and interstitial fluid (ISF) affect CNS function, the regulatory system remains to be fully understood. Therefore, the purpose of this study was to investigate d-serine transport across the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) and in brain parenchymal cells. d-Serine microinjected into the cerebrum was not eliminated, suggesting a negligible contribution of d-serine efflux transport at the BBB. In contrast, d-serine was taken up from the circulating blood across the BBB via a carrier-mediated process. d-Serine elimination clearance from CSF was fourfold greater than that of d-mannitol, which is considered to reflect CSF bulk flow. The characteristics of d-serine uptake by isolated choroid plexus were consistent with those of Na⁺-independent alanine-serine-cysteine transporter 1 (asc-1). Uptake of D-serine by brain slices appeared to occur predominantly via asc-1 and Na⁺-dependent alanine-serine-cysteine transporter 2. These findings suggest that the regulatory system of d-serine levels in ISF and CSF involves (i) asc-1 at the BCSFB, acting as a major pathway of d-serine elimination from the CSF, (ii) blood-to-brain and blood-to-CSF influx transport of d-serine across the BBB and BCSFB, and (iii) concentrative uptake of d-serine by brain parenchymal cells.