Ph.D Thesis


Ph.D StudentSafory Hazem
SubjectThe Asc-1 Transporter Regulates Glycine/D-Serine Metabolism
and Glycinergic Inhibitory Neurotransmission in
Motor Neurons: Implications for
Hyperekplexia Disorders
DepartmentDepartment of Medicine
Supervisor PROF. Herman Wolosker
Full Thesis textFull thesis text - English Version


Abstract

Asc1 (slc7a10) is a plasma membrane antiporter present in neurons that has high affinity for small neutral amino acids, such as glycine, Lserine, Dserine, 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. Asc1 knockout mice exhibit longlasting 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 Asc1 in neurotransmitter metabolism by studying Asc1 knockout (KO) mice. Using metabolomics, biochemical and electrophysiological and behavioral methods, we demonstrated that Asc1KO mice exhibit a selective decrease in glycine levels in the brain and spinal cord, impaired glycinergic inhibitory transmission, and a hyperekplexialike phenotype that is rescued by replenishing brain glycine. Asc1 works as a glycine and Lserine transporter, and its transport activity is required for the subsequent conversion of Lserine into glycine in vivo. Our data indicate that Asc1 is a previously undescribed pivotal regulator of glycine metabolism and a novel candidate for hyperekplexia disorders.