|Ph.D Student||Safory Hazem|
|Subject||The Asc-1 Transporter Regulates Glycine/D-Serine Metabolism|
and Glycinergic Inhibitory Neurotransmission in
Motor Neurons: Implications for
|Department||Department of Medicine||Supervisor||PROF. Herman Wolosker|
|Full Thesis text|
Asc‐1 (slc7a10) is a plasma membrane antiporter present in neurons that has high affinity for small neutral amino acids, such as glycine, L‐serine, D‐serine, L-alanine, and L-cysteine. Several studies have depicted Asc-1 as a regulator of D-serine release from neurons, and that subsequently it mediates NMDA receptors (NMDARs) activation. Asc‐1 knockout mice exhibit long‐lasting tremors and convulsions that start in the second postnatal week and are associated with an early postnatal death. Since Asc-1 has several substrates, it has been unclear how deletion of this transporter causes the neurological phenotype and how it affects amino acid and neurotransmitter metabolism.
In our study, we have investigated the role of Asc‐1 in neurotransmitter metabolism by studying Asc‐1 knockout (KO) mice. Using metabolomics, biochemical and electrophysiological and behavioral methods, we demonstrated that Asc‐1‐KO mice exhibit a selective decrease in glycine levels in the brain and spinal cord, impaired glycinergic inhibitory transmission, and a hyperekplexia‐like phenotype that is rescued by replenishing brain glycine. Asc‐1 works as a glycine and L‐serine transporter, and its transport activity is required for the subsequent conversion of L‐serine into glycine in vivo. Our data indicate that Asc‐1 is a previously undescribed pivotal regulator of glycine metabolism and a novel candidate for hyperekplexia disorders.