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In the mammalian central nervous system, transporter-mediated reuptake may be critical for terminating the neurotransmitter action ofd-serine at the strychnine insensitive glycine site of the NMDA receptor. The Na+ independent amino acid transporter alanine–serine–cysteine transporter 1 (Asc-1) has been proposed to account for synaptosomald-serine uptake by virtue of its high affinity ford-serine and widespread neuronal expression throughout the brain. Here, we sought to validate the contribution of Asc-1 tod-serine uptake in mouse brain synaptosomes using Asc-1 gene knockout (KO) mice. Total [3H]d-serine uptake in forebrain and cerebellar synaptosomes from Asc-1 knockout mice was reduced to 34 ± 5% and 22 ± 3% of that observed in wildtype (WT) mice, respectively. When the Na+ dependent transport components were removed by omission of Na+ ions in the assay buffer,d-serine uptake in knockout mice was reduced to 8 ± 1% and 3 ± 1% of that measured in wildtype mice in forebrain and cerebellum, respectively, suggesting Asc-1 plays a major role in the Na+ independent transport ofd-serine. Potency determination ofd-serine uptake showed that Asc-1 mediated rapid high affinity Na+ independent uptake with an IC50 of 19 ± 1 µm. The remaining uptake was mediated predominantly via a low affinity Na+ dependent transporter with an IC50 of 670 ± 300 µm that we propose is the glial alanine–serine–cysteine transporter 2 (ASCT2) transporter. The results presented reveal that Asc-1 is the only high affinityd-serine transporter in the mouse CNS and is the predominant mechanism ford-serine reuptake. [ABSTRACT FROM AUTHOR]

Abstract: Schizophrenia is a chronic and debilitating disease which is thought to arise from a neuro-developmental disorder. Both the stable tubule-only polypeptide (STOP) protein and the N-methyl-d-aspartate (NMDA) NR1 subunit are involved in neuronal development and physiology. It has therefore been postulated that transgenic mice lacking either the STOP or the NMDAR1 gene would show a ‘schizophrenic-like’ phenotype. Here, STOP knockout and NMDA NR1 hypomorphic mice were assessed in a behavioural measure that can be used to detect schizophrenic-like phenotypes: a change in sensorimotor gating, measured through prepulse inhibition (PPI). STOP knockout mice were further assessed in another measure of ‘schizophrenic-like behaviour’: hyperlocomotion. The PPI deficit exhibited by both the STOP knockout and NMDA knockdown mice could not be reversed by acute treatment with the atyptical antipsychotic, clozapine (1mg/kg, i.p.) but the hyperlocomotion shown by the STOP knockout mice was reversed with the same acute dose of clozapine. [Copyright &y& Elsevier]