ArticleProceedings of the National Academy of Sciences of the United States of America2019
The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers.
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Who cites it
84 citing papers in PubMed, 138 citations in OpenAlex.
- Article
- Astrocytic PI3Kα controls synaptic plasticity and cognitive function via serine metabolism.Nature communications · 2026Article
- Biomolecular and cellular chirality: Novel diagnostic perspectives for diseases.APL bioengineering · 2026Review
- A mitochondrial-neuroinflammation-D-serine connection in epilepsy.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Cognitive loss after brain trauma results from sex-specific activation of synaptic pruning processes.Brain : a journal of neurology · 2026Article
- Manual therapy ameliorates neuromuscular dysfunction in spastic model rat: involvement of the C-Fiber-mediated CaMKII pathway.Frontiers in neuroscience · 2026Article
- PHGDH-mediated serine synthesis reduces oligodendrocyte death by sustaining GSH and NADPH levels after brain ischemia.Frontiers in pharmacology · 2026Article
- The neuron-astrocyte metabolic unit as a cornerstone of brain energy metabolism in health and disease.Nature metabolism · 2025Review
- Glycine Reverses Behavioral Deficits in a Mouse Model for Psychosis With 4 Copies of the Gldc Gene.Pharmacology research & perspectives · 2025Article
- Pharmacological inhibition of PSPH reduces serine levels and epileptic seizures.Nature chemical biology · 2025Article
- CLN5 deficiency impairs glucose uptake and uncovers PHGDH as a potential biomarker in Batten disease.Molecular psychiatry · 2025Article
- Differential Astrocyte-Supplied NMDAR Co-Agonist for CA1 Versus Dentate Gyrus Long-Term Potentiation.Hippocampus · 2025Article
- d-amino acids: new functional insights.The FEBS journal · 2025Review
- Article
- Mammalian Tolerance to Amino Acid Heterochirality.Chembiochem : a European journal of chemical biology · 2025Review
- Neural Metabolic Networks: Key Elements of Healthy Brain Function.Journal of neurochemistry · 2025Review
- α-Hydrazino Acids Inhibit Pyridoxal Phosphate-Dependent Decarboxylases via "Catalytically Correct" Ketoenamine Tautomers: A Special Motif for Chemical Biology and Drug Discovery?ACS catalysis · 2025Article
- Early involvement of D-serine in β-amyloid-dependent pathophysiology.Cellular and molecular life sciences : CMLS · 2025Article
- DTD1 modulates synaptic efficacy by maintaining D-serine and D-aspartate homeostasis.Science China. Life sciences · 2025Article
- mGluR5 as a Potential Orchestrator of Astrocyte Interactions in Neurological Disorders.Neural plasticity · 2025Review
24 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Astrocytes express the 3-phosphoglycerate dehydrogenase (Phgdh) enzyme required for the synthesis of l-serine from glucose. Astrocytic l-serine was proposed to regulate NMDAR activity by shuttling to neurons to sustain d-serine production, but this hypothesis remains untested. We now report that inhibition of astrocytic Phgdh suppressed the de novo synthesis of l-and d-serine and reduced the NMDAR synaptic potentials and long-term potentiation (LTP) at the Schaffer collaterals-CA1 synapse. Likewise, enzymatic removal of extracellular l-serine impaired LTP, supporting an l-serine shuttle mechanism between glia and neurons in generating the NMDAR coagonist d-serine. Moreover, deletion of serine racemase (SR) in glutamatergic neurons abrogated d-serine synthesis to the same extent as Phgdh inhibition, suggesting that neurons are the predominant source of the newly synthesized d-serine. We also found that the synaptic NMDAR activation in adult SR-knockout (KO) mice requires Phgdh-derived glycine, despite the sharp decline in the postnatal glycine levels as a result of the emergence of the glycine cleavage system. Unexpectedly, we also discovered that glycine regulates d-serine metabolism by a dual mechanism. The first consists of tonic inhibition of SR by intracellular glycine observed in vitro, primary cultures, and in vivo microdialysis. The second involves a transient glycine-induce d-serine release through the Asc-1 transporter, an effect abolished in Asc-1 KO mice and diminished by deleting SR in glutamatergic neurons. Our observations suggest that glycine is a multifaceted regulator of d-serine metabolism and implicate both d-serine and glycine in mediating NMDAR synaptic activation at the mature hippocampus through a Phgdh-dependent shuttle mechanism.
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