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

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.