Deficiencia de SLC38A3 revela un papel crítico de la glutamina derivada de la sangre en el desarrollo cerebral

Biallelic mutations in SLC38A3 lead to postnatal progressive microcephaly, epilepsy, and intellectual disability. However, the underlying pathophysiology remains unknown. Here, we identified Slc38a3 expressed at the vascular endothelium as a critical glutamine transporter that mediates blood-to-brain influx of glutamine through the blood-brain barrier (BBB). Endothelial selective deletion of Slc38a3 (Slc38a3-cKO) lowered the influx of glutamine across the BBB and decreased brain glutamine levels in mouse pups. This was associated with lower transfer of glutamine carbons to glutamate and GABA, suggesting impairment of the glutamine-glutamate/GABA metabolic cycle. Like individuals with mutations in SLC38A3, Slc38a3-cKO pups developed postnatal progressive microcephaly as well as behavioural impairments and morphological alterations in synapses. Approximately 30% of Slc38a3-cKO pups fail to thrive, exhibiting motor dysfunction and preweaning lethality. Glutamine deficiency in the Slc38a3-cKO hippocampus was associated with a slower TCA cycle and a seemingly adaptive increase in glycolysis rate. Glutamine supplementation replenished brain glutamine, prevented microcephaly, and normalized motor behavior in Slc38a3-cKO pups, indicating that brain glutamine deficiency is the primary cause of the phenotype. In contrast to the dogma that all glutamine is produced locally in the brain, our data show that Slc38a3 provides blood-derived glutamine for neurotransmitter synthesis, energy metabolism, and synaptogenesis. Our findings suggest that SLC38A3 mutations cause a glutamine-related BBB aminoacidopathy and developmental disorder, which may be amenable to glutamine supplementation therapy.