Since the finding by [Johnson and Ascher (1987)][1] demonstrating that glycine enhances electrophysiological responses mediated by N-methyl-d-aspartate (NMDA)b-sensitive glutamatergic receptors, considerable interest has been devoted to this topic (for reviews, see [Dingledine et al. , 1990][2]; [

Glycine and N-Methyl-d-Aspartate Receptors: Physiological Significance and Possible Therapeutic Applications

Together with aspartate, glutamate is the major excitatory neurotransmitter in the brain. Glutamate binds and activates both ligand-gated ion channels (ionotropic glutamate receptors) and a class of G-protein coupled receptors (metabotropic glutamate receptors). Although the intracellular glutamate concentration in the brain is in the millimolar range, the extracellular glutamate concentration is kept in the low micromolar range by the action of excitatory amino acid transporters that import glutamate and aspartate into astrocytes and neurons. Excess extracellular glutamate may lead to excitotoxicity in vitro and in vivo in acute insults like ischemic stroke via the overactivation of ionotropic glutamate receptors. In addition, chronic excitotoxicity has been hypothesized to play a role in numerous neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. Based on this hypothesis, a good deal of effort has been devoted to develop and test drugs that either inhibit glutamate receptors or decrease extracellular glutamate. In this review, we provide an overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration. In addition, we summarize the available experimental evidence for glutamate toxicity in animal models of neurodegenerative diseases.

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Chronic Glutamate Toxicity in Neurodegenerative Diseases—What is the Evidence?

D-Serine is localized in mammalian brain to a discrete population of glial cells near NMDA receptors, suggesting that D-serine is an endogenous agonist of the receptor-associated glycine site. To explore this possibility, we have compared the immunohistochemical localizations of D-serine, glycine, and NMDA receptors in rat brain. In the telencephalon, D-serine is concentrated in protoplasmic astrocytes, which are abundant in neuropil in close vicinity to NMDA receptor 2A/B subunits. Ultrastructural examination of the CA1 region of hippocampus reveals D-serine in the cytosolic matrix of astrocytes that ensheath neurons and blood vessels, whereas NR2A/B is concentrated in dendritic spines. By contrast, glycine immunoreactivity in telencephalon is the lowest in brain. During postnatal week 2, D-serine levels in cerebellum are comparable to those in adult cerebral cortex but fall to undetectable levels by day 26. During week 2, we observe parallel ontogeny of D-serine in Bergmann glia and NR2A/B in Purkinje cells, suggesting a role for astrocytic D-serine in NMDA receptor-mediated synaptogenesis. D-Serine in the radial processes of Bergmann glia is also well positioned to regulate NMDA receptor-dependent granule cell migration. In the inner granule layer, D-serine is found transiently in protoplasmic astrocytes surrounding glomeruli, where it could regulate development of the mossy fiber/granule cell synapse. D-Serine seems to be the endogenous ligand of glycine sites in the telencephalon and developing cerebellum, whereas glycine predominates in the adult cerebellum, olfactory bulb, and hindbrain.

https://www.jneurosci.org/content/jneuro/17/5/1604.full.pdf

d-Serine as a Neuromodulator: Regional and Developmental Localizations in Rat Brain Glia Resemble NMDA Receptors

Free D-aspartate and D-serine in the mammalian brain and periphery.

Atypical neural messengers.

We have analyzed free chiral amino acids (aspartate and serine) in the human frontal cortex at different ontogenic stages (from 14 weeks of gestation to 101 years of age) by HPLC with fluorometric detection after derivatization with N-tert-butyl-oxycarbonyl-L-cysteine and o-phthaldialdehyde. Exceptionally high levels of free D-aspartate and D-serine were demonstrated in the fetal cortex at gestational week 14. The ratios of D-aspartate and of D-serine to the total corresponding amino acids were also high, at 0.63 and 0.27, respectively. The concentration of D-aspartate dramatically decreased to a trace level by gestational week 41 and then remained very low during all postnatal stages. In contrast, the frontal tip contained persistently high levels of D-serine throughout embryonic and postnatal life, whereas the D-amino acid content in adolescents and aged individuals was about half of that in the fetuses. Because D-aspartate and D-serine are known to have selective actions at the NMDA-type excitatory amino acid receptor, the present data suggest that these D-amino acids might play a pivotal role in cerebral development and functions that are related to the NMDA receptor.

Eiji Ootomo

Papers

Embryonic Development and Postnatal Changes in Free d‐Aspartate and d‐Serine in the Human Prefrontal Cortex