Ph.D Thesis

Ph.D StudentSason-Bauer Hagit
SubjectRole of the Brain Transporters Asc-1 and ASCT1 in D-Serine
Homeostasis; Synaptic Activity and Behavior
DepartmentDepartment of Medicine
Supervisors PROF. Herman Wolosker
ASSOCIATE PROF. Avraham Avital
Full Thesis textFull thesis text - English Version


____________________________________________________________________ d-Serine is a physiologic regulator of NMDA receptor (NMDAR) activity but its release mechanisms are yet to be fully elucidated. d-Serine dynamics is regulated by the Asc-1 (SLC7a10), a neuronal transporter that exchanges d-serine for small neutral amino acids. In order to gain insight into the physiological role and the direction of Asc-1-mediated d-serine fluxes we developed a selective Asc-1 blocker. The inhibitor blocks Asc-1 without stimulating the amino acid hetero-exchange, and does not affect glycine transporters or other putative d-serine transporters. We show that Asc-1 blockade decreases both basal and hetero-exchange-mediated d-serine release from primary neuronal cultures and neocortical slices. d-Serine release rate is reduced in slices from Asc-1-KO mice, confirming the role of Asc-1 in d-serine release. Asc-1 inhibition decreases the expression of NMDAR-dependent long-term potentiation of synaptic activity at the hippocampal CA1 from adult rats, and this effect is preventable by adding exogenous d-serine. Our data demonstrate that Asc-1 mediates tonic co-agonist release, which is required for optimal NMDAR activation and synaptic plasticity. An additional aspect of our work deals with the role of ASCT1 (SLC1a4) in d-serine homeostasis. We established new ASCT1-KO mice and found that they display altered l- and d-serine homeostasis. Immunofluorescence studies demonstrated glial, but not neuronal expression, and the signal was absent in ASCT1-KO sections. Behavioral tests point to possible lower anxiety in ASCT1-KO mice, suggesting a novel role of this transporter in glial-neuron crosstalk.