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

<span class="paragraphSection"><div class="boxTitle">Abstract</div><span style="text-transform:lowercase;font-variant:small-caps;">d</span>-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 <span style="text-transform:lowercase;font-variant:small-caps;">d</span>-serine and glycine. Asc-1 operates as a facilitative transporter and as an antiporter, though the preferred direction of <span style="text-transform:lowercase;font-variant:small-caps;">d</span>-serine transport is uncertain. We developed a selective Asc-1 blocker, Lu AE00527, that blocks <span style="text-transform:lowercase;font-variant:small-caps;">d</span>-serine release mediated by all the transport modes of Asc-1 in primary cultures and neocortical slices. Furthermore, <span style="text-transform:lowercase;font-variant:small-caps;">d</span>-serine release is reduced in slices from Asc-1 knockout (KO) mice, indicating that <span style="text-transform:lowercase;font-variant:small-caps;">d</span>-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.</span>

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