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 Nmethyl-D-aspartate (NMDA) subtype of glutamate receptors, in several nervous tissues, including the developing cerebellum and the retina. Here, we examined whether endogenous Dserine 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 overactivation in the cerebral cortex.

NMDA- and β-Amyloid1–42-Induced Neurotoxicity Is Attenuated in Serine Racemase Knock-Out Mice

“…In this slice culture system, despite the high glycine levels in the medium, removal of endogenous D-serine completely abolishes NMDA neurotoxicity. However, another study demonstrated that the cytotoxicity of NMDA on rat cerebrocortical slice cultures is potentiated by addition of both glycine and D-serine (Katsuki et al, 2004). We have shown that SR is predominantly localized in forebrain neurons, and that the expression pattern of SR changes under the culture condition (Miya et al, 2008).…”

D-Serine Is the Dominant Endogenous Coagonist for NMDA Receptor Neurotoxicity in Organotypic Hippocampal Slices

“…The modest effect of D-amino acid oxidase to remove D-serine from slices has been attributed to limited penetration of the enzyme in the tissue (Mothet et al, 2000). A partial protection against NMDA toxicity by D-amino acid oxidase treatment in corticostriatal slices was reported recently (Katsuki et al, 2004). In this preliminary account, the authors did not monitor endogenous D-serine or glycine levels and provided no indication that the treatment decreased D-serine.…”

Enhanced astrocytic d-serine underlies synaptic damage after traumatic brain injury

“…Conversely, recent studies indicate that only a small percentage of astrocytes express a negligible amount of SRR in rodent forebrain tissues (21). Pathological levels of d-serine, similarly to glutamate, have been implicated in mediating acute excito toxic cell death during pathological conditions (22)(23)(24)(25)(26); however, the effect of prolonged increases in d-serine levels on synaptic function remains to be determined.…”