Asc-1 Transporter Regulation of Synaptic Activity via the Tonic Release of d-Serine in the Forebrain.
Cereb Cortex
; 27(2): 1573-1587, 2017 02 01.
Article
en En
| MEDLINE
| ID: mdl-26796213
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sinapsis
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Prosencéfalo
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Potenciación a Largo Plazo
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Sistema de Transporte de Aminoácidos y/
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Plasticidad Neuronal
Límite:
Animals
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Humans
Idioma:
En
Revista:
Cereb Cortex
Asunto de la revista:
CEREBRO
Año:
2017
Tipo del documento:
Article
País de afiliación:
Israel