title: Asc-1 Transporter Regulation of Synaptic Activity via the Tonic Release of d-Serine in the Forebrain.
abstract: d-Serine is a co-agonist of NMDA receptors (NMDARs) whose activity is potentially regulated by Asc-1 (SLC7A10), a transporter that displays high affinity for d-serine and glycine. Asc-1 operates as a facilitative transporter and as an antiporter, though the preferred direction of d-serine transport is uncertain. We developed a selective Asc-1 blocker, Lu AE00527, that blocks d-serine release mediated by all the transport modes of Asc-1 in primary cultures and neocortical slices. Furthermore, d-serine release is reduced in slices from Asc-1 knockout (KO) mice, indicating that d-serine efflux is the preferred direction of Asc-1. The selectivity of Lu AE00527 is assured by the lack of effect on slices from Asc-1-KO mice, and the lack of interaction with the co-agonist site of NMDARs. Moreover, in vivo injection of Lu AE00527 in P-glycoprotein-deficient mice recapitulates a hyperekplexia-like phenotype similar to that in Asc-1-KO mice. In slices, Lu AE00527 decreases the long-term potentiation at the Schaffer collateral-CA1 synapses, but does not affect the long-term depression. Lu AE00527 blocks NMDAR synaptic potentials when typical Asc-1 extracellular substrates are present, but it does not affect AMPAR transmission. Our data demonstrate that Asc-1 mediates tonic co-agonist release, which is required for optimal NMDAR activation and synaptic plasticity.
authors.affiliation: Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Hagit
authors.initials: H
authors.lastname: Sason
authors.affiliation: UMR894, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Billard
authors.affiliation: Drug Discovery Neuroscience, H. Lundbeck A/S, DK-2500 Valby, Denmark.
authors.forename: Garrick Paul
authors.initials: GP
authors.lastname: Smith
authors.affiliation: Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Hazem
authors.initials: H
authors.lastname: Safory
authors.affiliation: Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Samah
authors.initials: S
authors.lastname: Neame
authors.affiliation: Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Eitan
authors.initials: E
authors.lastname: Kaplan
authors.affiliation: Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Rosenberg
authors.affiliation: Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Salman
authors.initials: S
authors.lastname: Zubedat
authors.affiliation: Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Veronika N
authors.initials: VN
authors.lastname: Foltyn
authors.affiliation: Drug Discovery Neuroscience, H. Lundbeck A/S, DK-2500 Valby, Denmark.
authors.forename: Claus Tornby
authors.initials: CT
authors.lastname: Christoffersen
authors.affiliation: Drug Discovery Neuroscience, H. Lundbeck A/S, DK-2500 Valby, Denmark.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bundgaard
authors.affiliation: Drug Discovery Neuroscience, H. Lundbeck A/S, DK-2500 Valby, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Thomsen
authors.affiliation: Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.|Emek Medical Center, Afula, Israel.
authors.forename: Avi
authors.initials: A
authors.lastname: Avital
authors.affiliation: Drug Discovery Neuroscience, H. Lundbeck A/S, DK-2500 Valby, Denmark.
authors.forename: Kenneth Vielsted
authors.initials: KV
authors.lastname: Christensen
authors.affiliation: Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Herman
authors.initials: H
authors.lastname: Wolosker
mesh_terms: D027182:Amino Acid Transport System y+ / Q000235:genetics*; D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology*; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D016548:Prosencephalon / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D027182:Amino Acid Transport System y+; D016194:Receptors, N-Methyl-D-Aspartate; C412624:Slc7a10 protein, mouse
keywords: NMDA receptor; glycine; long-term potentiation; neurodegeneration; synaptic plasticity