Asc-1 Transporter Regulation of Synaptic Activity via the Tonic Release of d-Serine in the Forebrain

• Published in: Cerebral cortex (New York, N.Y. 1991) Vol. 27; no. 2; pp. 1573 - 1587
• Main Authors: Sason, Hagit, Billard, Jean Marie, Smith, Garrick Paul, Safory, Hazem, Neame, Samah, Kaplan, Eitan, Rosenberg, Dina, Zubedat, Salman, Foltyn, Veronika N, Christoffersen, Claus Tornby, Bundgaard, Christoffer, Thomsen, Christian, Avital, Avi, Christensen, Kenneth Vielsted, Wolosker, Herman
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press (OUP) 01.02.2017
• Subjects: Amino Acid Transport System y+ - genetics; Animals; Excitatory Postsynaptic Potentials - physiology; Humans; Life Sciences; Long-Term Potentiation - physiology; Mice, Knockout; Neuronal Plasticity - physiology; Neurons - physiology; Neurons and Cognition; Prosencephalon - physiology; Receptors, N-Methyl-D-Aspartate - metabolism; Synapses - physiology; Synaptic Transmission - physiology; neurodegeneration; synaptic plasticity; NMDA receptor; glycine; long-term potentiation
• ISSN: 1047-3211; 1460-2199
• DOI: 10.1093/cercor/bhv350

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.