A new type of blood-brain barrier aminoacidopathy underlies metabolic microcephaly associated with SLC1A4 mutations.

Mutations in the SLC1A4 transporter lead to neurodevelopmental impairments, spastic tetraplegia, thin corpus callosum and microcephaly in children. SLC1A4 catalyses obligatory amino acid exchange between neutral amino acids, but the physiopathology of SLC1A4 disease mutations and progressive microcephaly remain unclear. Here, we examined the phenotype and metabolic profile of three Slc1a4 mouse models: a constitutive Slc1a4-knockout mouse; a knock-in mouse with the major human Slc1a4 mutation (Slc1a4-K256E); and a selective knockout of Slc1a4 in brain endothelial cells (Slc1a4tie2-cre). We show that Slc1a4 is a bona fideL-serine transporter at the blood-brain barrier (BBB) and that acute inhibition or deletion of Slc1a4 leads to a decrease in serine influx into the brain. This results in microcephaly associated with decreased L-serine content in the brain, accumulation of atypical and cytotoxic 1-deoxysphingolipids, neurodegeneration, synaptic and mitochondrial abnormalities and behavioural impairments. Prenatal and early postnatal oral administration of L-serine at levels that replenish the serine pool in the brain rescued the observed biochemical and behavioural changes. Administration of L-serine until the second postnatal week also normalized brain weight in Slc1a4-E256K mice. Our observations suggest that the transport of 'non-essential' amino acids from the blood through the BBB is at least as important as that of essential amino acids for brain metabolism and development. We propose that SLC1A4 mutations cause a BBB aminoacidopathy with deficits in serine import across the BBB, required for optimal brain growth, leading to a metabolic microcephaly, which may be amenable to treatment with L-serine.