SLC38A2 mediates selective L-serine influx across the blood-brain barrier and controls brain D-serine and excitatory synapse development

L-Serine is essential for brain metabolism, serving as a precursor for the synthesis of the neuromodulator D-serine, glycine, and lipids. Contrary to the prevailing view that brain L-serine is derived exclusively from local synthesis, our findings demonstrate that dietary L-serine is required to maintain brain L-serine levels and the production of its downstream metabolites. Sphingolipidome analysis indicates that dietary restriction of serine/glycine leads to the formation of neurotoxic 1-deoxysphingolipids and affects the expression of circadian and endothelial cell genes in the hippocampus. We identified the glutamine transporter SLC38A2 as a selective L-serine transporter at the BBB that mediates the influx of circulating L-serine to the brain. Endothelial-selective Slc38a2 knockout (Slc38a2-cKO) decreased in vivo blood-to-brain L-serine influx and selectively lowered hippocampal L-serine and D-serine in mouse pups. Isotope tracing experiments confirmed reduced incorporation of L-serine into the brain of Slc38a2-cKO pups but revealed normal incorporation of L-glutamine, indicating that SLC38A2 does not use L-glutamine at this age. Serine-to-glycine conversion in Slc38a2-cKO pups was preserved, while the de novo synthesis of glycine from glucose was higher in the cerebral cortex. Slc38a2-cKO pups exhibited ultrastructural defects at excitatory synapses, including reduced synaptic vesicle cluster size and decreased postsynaptic density area. Immunoelectron microscopy demonstrated that SLC38A2 is localized to both the luminal and abluminal endothelial membranes, supporting a dual role for this transporter at the BBB. Luminal SLC38A2 appears to serve as a selective route for L-serine transport across the BBB during early postnatal development and is required for excitatory synapse maturation. In contrast, abluminal SLC38A2 is more consistent with a role in the equilibrative efflux of brain-derived SLC38A2 substrates. SLC38A2 inhibition may be beneficial for limiting D-serine accumulation in the brain, particularly in conditions with pathologically elevated D-serine levels, such as traumatic brain injury, epilepsy, and neurodegenerative disorders.