Received for publication May 6, 2004.
Revised June 26, 2004.
Accepted for publication July 7, 2004.

Endogenous D-serine is involved in induction of neuronal death by N-methyl-D-aspartate and simulated ischemia in rat cerebrocortical slices

Abstract

Emerging evidence indicates that D-serine rather than glycine serves as an endogenous agonist at glycine site of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, in several nervous tissues including the developing cerebellum and the retina. Here we examined if endogenous D-serine plays a significant role in neuronal damage resulting from excitotoxic insults in the cerebral cortex, using rat brain slices maintained in a defined salt solution. Neuronal cell death induced by application of NMDA or by oxygen-glucose deprivation (simulated ischemia) was markedly suppressed by a competitive glycine site antagonist 2,7-dichlorokynurenic acid. Addition of glycine or D-serine did not augment neuronal damage by NMDA or simulated ischemia, indicating that sufficient amount of glycine site agonist(s) is supplied endogenously within the slices. Application of D-amino acid oxidase, an enzyme that degrades D-serine, markedly inhibited neuronal damage by NMDA and simulated ischemia, which was reversed by addition of excess D-serine or glycine. Sensitivity to the glycine site antagonist of NMDA- or ischemia-induced damage was not affected by the presence of a non-NMDA receptor antagonist, suggesting that kainate receptor-stimulated D-serine release as demonstrated in primary cultured astrocytes does not contribute significantly to the extent of neuronal injury in these settings. The present results suggest that endogenous supply of D-serine as a glycine site agonist is important for neuronal injury involving NMDA receptor over-activation in the cerebral cortex.

Key words: Brain Slice, D-serine, Excitotoxicity, Glycine Site, Ischemia, NMDA receptor

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