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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\u2013brain barrier.<\/jats:p>\n                  <jats:p>Endothelial selective deletion of Slc38a3 (Slc38a3-cKO) lowered the influx of glutamine across the blood\u2013brain barrier 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\u2013glutamate\/GABA metabolic cycle. Like individuals with mutations in SLC38A3, Slc38a3-cKO pups developed postnatal progressive microcephaly, in addition to behavioural impairments and morphological alterations in synapses. Approximately 30% of Slc38a3-cKO pups failed to thrive, exhibiting motor dysfunction and preweaning lethality. Glutamine deficiency in the Slc38a3-cKO hippocampus was associated with a slower tricarboxylic acid cycle and a seemingly adaptive increase in glycolysis rate. Glutamine supplementation replenished brain glutamine, prevented microcephaly and normalized motor behaviour in Slc38a3-cKO pups, indicating that brain glutamine deficiency is the primary cause of the phenotype.<\/jats:p>\n                  <jats:p>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 blood\u2013brain barrier aminoacidopathy and developmental disorder, which might be amenable to glutamine supplementation therapy.<\/jats:p>","DOI":"10.1093\/brain\/awaf473","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T12:48:09Z","timestamp":1766494089000},"page":"2747-2759","source":"Crossref","is-referenced-by-count":4,"title":["SLC38A3 deficiency reveals a critical role of blood-derived glutamine in brain development"],"prefix":"10.1093","volume":"149","author":[{"given":"Inna","family":"Radzishevsky","sequence":"first","affiliation":[{"name":"The Ruth and Bruce Rappaport Faculty of Medicine, Department of Biochemistry, Technion-Israel Institute of Technology , Haifa 3525433 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lama","family":"Harb","sequence":"additional","affiliation":[{"name":"The Ruth and Bruce Rappaport Faculty of 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