The presence of free D-aspartic acid in rodents and man

Dunlop, David S.; Neidle, Amos; McHale, Denise M.; Lajtha, Ábel

doi:10.1016/s0006-291x(86)80329-1

Cited by 313 publications

(200 citation statements)

References 7 publications

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“…Based on these considerations, the initial observation of Lajtha and colleagues of D-aspartate in mammalian tissues was surprising (Dunlop et al, 1986). In newborn rodents, D-aspartate levels are highest in the cerebral cortex and diminish with age.…”

Section: Introductionmentioning

confidence: 99%

D-Serine as a putative glial neurotransmitter

2004

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Abundant recent evidence favors a neurotransmitter/neuromodulator role for D-serine. D-serine is synthesized from L-serine by serine racemase in astrocytic glia that ensheath synapses, especially in regions of the brain that are enriched in NMDA-glutamate receptors. D-serine is more potent than glycine at activating the 'glycine' site of these receptors. Moreover, selective degradation of D-serine but not glycine by D-amino acid oxidase markedly reduces NMDA neurotransmission. D-serine appears to be released physiologically in response to activation by glutamate of AMPA-glutamate receptors on D-serine-containing glia. This causes glutamate-receptor-interacting protein, which binds serine racemase, to stimulate enzyme activity and D-serine release. Thus, glutamate triggers the release of D-serine so that the two amino acids can act together on postsynaptic NMDA receptors. D-serine also plays a role in neural development, being released from Bergmann glia to chemokinetically enhance the migration of granule cell cerebellar neurons from the external to the internal granular layer.

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Section: Introductionmentioning

confidence: 99%

D-Serine as a putative glial neurotransmitter

2004

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“…The neurobiology of such odd chiral molecules reveals new mechanisms to modulate neurotransmission and also established the conservation of d-amino acid metabolism in mammals. Lajtha and coworkers first detected the presence of high levels of free d-aspartate in the rat and human brain (Dunlop et al, 1986). Subsequently, Hashimoto et al discovered remarkable quantities of d-serine in mammalian brain at levels even higher than some l-amino acids (Hashimoto et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Neurobiology through the looking-glass: d-serine as a new glial-derived transmitter

Wolosker

Panizzutti

Miranda

2002

Neurochemistry International

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“…Deletion of serine racemase alters NMDA receptor neurotransmission and long-term potentiation (2)(3)(4), and its disturbance has been implicated in schizophrenia (5)(6)(7). D-aspartate is present in selected neuronal populations in the brain as well as in neuroendocrine tissues, such as the catecholaminergic cells of the adrenal medulla, the anterior/posterior lobes of the pituitary gland, the pineal gland, and the testes (8)(9)(10). In early neonatal stages, high D-aspartate densities in the cortical plate, subventricular zone, and discrete portions of the hippocampal formation imply a developmental role (11).…”

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confidence: 99%

Aspartate racemase, generating neuronal D-aspartate, regulates adult neurogenesis

Kim

Duan

Huang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

129

128

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D-Aspartic acid is abundant in the developing brain. We have identified and cloned mammalian aspartate racemase (DR), which converts Laspartate to D-aspartate and colocalizes with D-aspartate in the brain and neuroendocrine tissues. Depletion of DR by retrovirus-mediated expression of short-hairpin RNA in newborn neurons of the adult hippocampus elicits profound defects in the dendritic development and survival of newborn neurons and survival. Because D-aspartate is a potential endogenous ligand for NMDA receptors, the loss of which elicits a phenotype resembling DR depletion, D-aspartate may function as a modulator of adult neurogenesis.neuronal development | neural progenitor cells | hippocampus | NMDA receptor | neuroendocrine D -amino acids are being increasingly recognized as putative neurotransmitters. D-serine, an endogenous ligand for the glutamate-NMDA receptor, is formed by serine racemase, a pyridoxal 5′-phosphate (PLP)-dependent enzyme that converts L-serine to D-serine (1). Deletion of serine racemase alters NMDA receptor neurotransmission and long-term potentiation (2-4), and its disturbance has been implicated in schizophrenia (5-7). D-aspartate is present in selected neuronal populations in the brain as well as in neuroendocrine tissues, such as the catecholaminergic cells of the adrenal medulla, the anterior/posterior lobes of the pituitary gland, the pineal gland, and the testes (8-10). In early neonatal stages, high D-aspartate densities in the cortical plate, subventricular zone, and discrete portions of the hippocampal formation imply a developmental role (11). In adult hippocampus, D-aspartate persists in dentate gyrus, where new neurons are generated throughout life (12, 13). These newborn neurons are integrated into existing neural circuitry and are involved in learning and memory formation (12, 13). Insight into specific neural functions for D-aspartate has been hampered by ignorance of its biosynthesis. In the present study, we identify and clone mammalian aspartate racemase (DR), which converts L-aspartate to D-aspartate. Deletion of DR leads to pronounced defects in adult hippocampal neurogenesis, implicating D-aspartate as a major regulator of neuronal development. Results and DiscussionCloning and Characterization of DR. In a genomic sequence analysis, we were unable to find candidate mammalian DR genes based on homology to serine racemase or bacterial aspartate racemases, which are either PLP-independent or PLP-dependent enzymes (14, 15). Vacca and coworkers (16-18) demonstrated that glutamate-oxalacetate transaminase (GOT) can generate small amounts of D-aspartate in the process of transaminating Laspartate to L-glutamate, and that formation of D-aspartate is augmented in GOT mutants, wherein histidine replaces tryptophan-140 and lysine replaces arginine-292. Tryptophan-140 normally prevents access of a proton donor, such as a water molecule, which can effectuate racemization (Fig. 1A); however, replacement of tryptophan-140 by histidine allows direct protonation by histidine for ...

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The presence of free D-aspartic acid in rodents and man

Cited by 313 publications

References 7 publications

D-Serine as a putative glial neurotransmitter

D-Serine as a putative glial neurotransmitter

Neurobiology through the looking-glass: d-serine as a new glial-derived transmitter

Aspartate racemase, generating neuronal D-aspartate, regulates adult neurogenesis

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