The amino acid transporter LAT1 coordinates proper motor function at the perinatal stage.

L-type amino acid transporter 1 (LAT1, encoded by Slc7a5) contributes to amino acid homeostasis and signaling in numerous cell types. Several lines of evidence implicate LAT1 in mammalian central nervous system development, but its functional significance in specific neuronal subtypes is largely unknown. Here, we demonstrate that LAT1/Slc7a5 expression in synapsin 1 (Syn1)-expressing neurons is essential for motor circuit development and motor coordination at the perinatal stage. Mice lacking Slc7a5 in Syn1-expressing neurons exhibited progressive motor coordination deficits and early postnatal lethality. These deficits were associated with selective degeneration of lower spinal motor neurons, reactive gliosis, skeletal muscle atrophy, and maldevelopment of neuromuscular junctions (NMJs), but no abnormalities in gross brain structure or neuronal viability. Pharmacological inhibition of apoptosis prolonged the survival of Slc7a5-deficient mice and reduced both lower motor neuron loss and NMJ maldevelopment. Furthermore, multi-cohort transcriptome analyses revealed inactivation of amino acid transport activity along with the downregulation of Slc7a5 expression in motor neurons of spinal muscular atrophy model mice. These results suggest that the amino acid transport system is essential for the survival and function of lower spinal motor neurons during early postnatal development, and identifies LAT1 as a potential therapeutic target for early-onset motor neuron diseases.