Endothelial SLC38A2 controls brain D-serine homeostasis and synapse development

L-serine is a precursor for the synthesis of the neuromodulator D-serine, glycine, and lipids. Contrary to the prevailing view that brain L-serine is exclusively derived from de novo synthesis, we demonstrate that dietary L-serine is required to maintain brain L-serine levels and prevents the formation of neurotoxic 1-deoxysphingolipids. We identified SLC38A2 as an L-serine transporter at the blood-brain barrier (BBB) that mediates the influx of circulating L-serine to the brain. Endothelial-selective Slc38a2 conditional knockout (Slc38a2-cKO) decreased in vivo blood-to-brain L-serine influx and selectively lowered hippocampal L-serine and D-serine in mouse pups. Immunoelectron microscopy demonstrated that SLC38A2 is localized to both the luminal and abluminal endothelial membranes. Slc38a2-cKO pups exhibited ultrastructural defects at excitatory synapses, including reduced synaptic vesicle cluster size and decreased postsynaptic density area. SLC38A2 inhibition may be beneficial for limiting D-serine accumulation in conditions with pathologically elevated L- or D-serine levels, such as traumatic brain injury and epilepsy.