NMDA- and β-Amyloid<sub>1–42</sub>-Induced Neurotoxicity Is Attenuated in Serine Racemase Knock-Out Mice

Inoue, Ran; Hashimoto, Kenji; Harai, Tomomi; Mori, Hisashi

doi:10.1523/jneurosci.5034-08.2008

Cited by 147 publications

(122 citation statements)

References 31 publications

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“…7). Recent studies using knock-out/mutant mice demonstrated that Srr deletion resulted in marked decreases in brain D-serine, which was associated with attenuation of NMDA receptormediated neurotransmission (31) and neurotoxicity (30,58). In addition, behavioral deficits were evident in two strains of these mutant mice (31,32), although the detailed behavioral phenotypes did not coincide with each other.…”

Section: Discussionmentioning

confidence: 99%

Brain-specific Phgdh Deletion Reveals a Pivotal Role for l-Serine Biosynthesis in Controlling the Level of d-Serine, an N-methyl-d-aspartate Receptor Co-agonist, in Adult Brain

Yang

Wada

Yoshida

et al. 2010

Journal of Biological Chemistry

117

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In mammalian brain, D-serine is synthesized from L-serine by serine racemase, and it functions as an obligatory coagonist at the glycine modulatory site of N-methyl-D-aspartate (NMDA)-selective glutamate receptors. Although diminution in D-serine level has been implicated in NMDA receptor hypofunction, which is thought to occur in schizophrenia, the source of the precursor L-serine and its role in D-serine metabolism in adult brain have yet to be determined. We investigated whether L-serine synthesized in brain via the phosphorylated pathway is essential for Dserine synthesis by generating mice with a conditional deletion of D-3-phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95). This enzyme catalyzes the first step in L-serine synthesis via the phosphorylated pathway. HPLC analysis of serine enantiomers demonstrated that both L-and D-serine levels were markedly decreased in the cerebral cortex and hippocampus of conditional knock-out mice, whereas the serine deficiency did not alter protein expression levels of serine racemase and NMDA receptor subunits in these regions. The present study provides definitive proof that Lserine-synthesized endogenously via the phosphorylated pathway is a key rate-limiting factor for maintaining steadystate levels of D-serine in adult brain. Furthermore, NMDAevoked transcription of Arc, an immediate early gene, was diminished in the hippocampus of conditional knock-out mice. Thus, this study demonstrates that in mature neuronal circuits L-serine availability determines the rate of Dserine synthesis in the forebrain and controls NMDA receptor function at least in the hippocampus.Glutamate is the principal excitatory neurotransmitter in mammalian brain, acting on ionotropic and metabotropic glutamate receptors. Ionotropic glutamate receptors can be divided into three classes based on their preference for the ligands N-methyl-D-aspartate (NMDA), 3 ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, and kainate. Among these receptors, NMDA receptors have been implicated in synapse refinement, synaptic plasticity, and learning/memory as well as brain pathologies including excitotoxicity and psychiatric diseases (for review, see Refs. 1-3). Two NMDA receptor subunits, NR1 and NR2, form tetramers that comprise the functional receptors. For the NMDA receptor to function as a ligand-gated ion channel, a co-agonist must occupy the glycine modulatory site on NR1 coincident with glutamate binding to the transmitter recognition site on NR2 (4 -6).D-Serine occurs naturally in the adult brain of higher vertebrates and is particularly enriched in forebrain regions (7). This D-amino acid acts as an endogenous co-agonist at the glycine modulatory site of NMDA receptors (for review, see Refs. 8 -11). In the telencephalon, where D-serine is abundant (12), its distribution pattern resembles that of NR2A/B subunits (13). In contrast, immunoreactivity for free glycine is very low in telencephalon and is detected primarily in the hindbrain and hypothalamus, where NR2A/B expression is weaker than in ...

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Section: Discussionmentioning

confidence: 99%

Brain-specific Phgdh Deletion Reveals a Pivotal Role for l-Serine Biosynthesis in Controlling the Level of d-Serine, an N-methyl-d-aspartate Receptor Co-agonist, in Adult Brain

Yang

Wada

Yoshida

et al. 2010

Journal of Biological Chemistry

117

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“…D-Serine is endogenously converted from L-serine by serine racemase (SRR) (5) and exists at a high level in the forebrain, where it has a critical role in long-term potentiation (6) and is required for memory formation (6). D-Serine is also involved in NMDAR-mediated neurotoxicity, a process that plays a pathophysiological role in stroke and neurodegenerative diseases (7)(8)(9). We previously reported that D-serine is increased in the spinal cord in both patients with sporadic/familial ALS and in a G93A-SOD1 mouse model of ALS (mSOD1 mouse) (10).…”

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confidence: 99%

d -Amino acid oxidase controls motoneuron degeneration through d -serine

Sasabe

Miyoshi

Suzuki

et al. 2011

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

182

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving an extensive loss of motoneurons. Aberrant excitability of motoneurons has been implicated in the pathogenesis of selective motoneuronal death in ALS. D-Serine, an endogenous coagonist of N-methyl-D-aspartate receptors, exacerbates motoneuronal death and is increased both in patients with sporadic/ familial ALS and in a G93A-SOD1 mouse model of ALS (mSOD1 mouse). More recently, a unique mutation in the D-amino acid oxidase (DAO) gene, encoding a D-serine degrading enzyme, was reported to be associated with classical familial ALS. However, whether DAO affects the motoneuronal phenotype and D-serine increase in ALS remains uncertain. Here, we show that genetic inactivation of DAO in mice reduces the number and size of lower motoneurons with axonal degeneration, and that suppressed DAO activity in reactive astrocytes in the reticulospinal tract, one of the major inputs to the lower motoneurons, predominantly contributes to the D-serine increase in the mSOD1 mouse. The DAO inactivity resulted from expressional down-regulation, which was reversed by inhibitors of a glutamate receptor and MEK, but not by those of inflammatory stimuli. Our findings provide evidence that DAO has a pivotal role in motoneuron degeneration through D-serine regulation and that inactivity of DAO is a common feature between the mSOD1 ALS mouse model and the mutant DAO-associated familial ALS. The therapeutic benefit of reducing D-serine or controlling DAO activity in ALS should be tested in future studies.excitotoxicity | motor neuron disease | neurodegeneration | enzyme histochemistry | 2D-HPLC A myotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective loss of motoneurons in the spinal cord and brain leading to fatal paralysis. Approximately 90% of all cases are sporadic, and the remaining cases are inherited. Of inherited cases, 20% are associated with mutations in superoxide dismutase 1 (SOD1), and 10% involves 43-kDa transactivation response DNA-binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS). Despite extensive studies of previously identified ALS-causing genes, the mechanism underlying the selective motoneuronal loss in ALS remains uncertain. Given that the mechanism is at least, in part, common between sporadic and familial ALS, identification of the common pathology is a clue to conquering ALS. Among numerous etiological hypotheses, motoneuronal vulnerability to excitotoxicity is one of the most intensely investigated targets for the treatment of ALS because it is observed in both sporadic and familial ALS with SOD1 mutations (1, 2). For motoneurons, glutamate is the main excitatory transmitter, and excessive motoneuron excitability by glutamate through ionotropic glutamate receptors has been demonstrated.The N-methyl-D-aspartate (NMDA) receptor (NMDAR) is a subtype of the ionotropic glutamate receptors and exhibits relatively higher permeability to the calcium ion (Ca ...

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“…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)(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).…”

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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.

131

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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NMDA- and β-Amyloid_1–42-Induced Neurotoxicity Is Attenuated in Serine Racemase Knock-Out Mice

Cited by 147 publications

References 31 publications

Brain-specific Phgdh Deletion Reveals a Pivotal Role for l-Serine Biosynthesis in Controlling the Level of d-Serine, an N-methyl-d-aspartate Receptor Co-agonist, in Adult Brain

Brain-specific Phgdh Deletion Reveals a Pivotal Role for l-Serine Biosynthesis in Controlling the Level of d-Serine, an N-methyl-d-aspartate Receptor Co-agonist, in Adult Brain

d -Amino acid oxidase controls motoneuron degeneration through d -serine

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

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

Cited by 147 publications

References 31 publications

Brain-specific Phgdh Deletion Reveals a Pivotal Role for l-Serine Biosynthesis in Controlling the Level of d-Serine, an N-methyl-d-aspartate Receptor Co-agonist, in Adult Brain

Brain-specific Phgdh Deletion Reveals a Pivotal Role for l-Serine Biosynthesis in Controlling the Level of d-Serine, an N-methyl-d-aspartate Receptor Co-agonist, in Adult Brain

d -Amino acid oxidase controls motoneuron degeneration through d -serine

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

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NMDA- and β-Amyloid_1–42-Induced Neurotoxicity Is Attenuated in Serine Racemase Knock-Out Mice