D-Serine Signaling and NMDAR-Mediated Synaptic Plasticity Are Regulated by System A-Type of Glutamine/D-Serine Dual Transporters
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D-serine is a physiologic coagonist of NMDA receptors (NMDARs) required for synaptic plasticity, but mechanisms that terminate D-serine signaling are unclear. In particular, the identity of unidirectional plasma membrane transporters that mediate D-serine reuptake has remained elusive. We report that D-serine and glutamine share the same neuronal transport system, consisting of the classic system A transporters Slc38a1 and Slc38a2. We show that these transporters are not saturated with glutamine in vivo and regulate the extracellular levels of D-serine and NMDAR activity. Glutamine increased the NMDAR-dependent long-term potentiation and the isolated NMDAR potentials at the Schaffer collateral–CA1 synapses, but without affecting basal neurotransmission in male mice. Glutamine did not increase the NMDAR potentials in slices from serine racemase knock-out mice, which are devoid of D-serine, indicating that the effect of glutamine is caused by outcompeting D-serine for a dual glutamine–D-serine transport system. Inhibition of the system A reduced the uptake of D-serine in synaptosomes and neuronal cultures of mice of either sex, while increasing the extracellular D-serine concentration in slices and in vivo by microdialysis. When compared with Slc38a2, the Slc38a1 transporter displayed more favorable kinetics toward the D-enantiomer. Biochemical experiments with synaptosomes from Slc38a1 knock-down mice of either sex further support its role as a D-serine reuptake system. Our study identifies the first concentrative and electrogenic transporters mediating D-serine reuptake in vivo. In addition to their classical role in the glutamine-glutamate cycle, system A transporters regulate the synaptic turnover of D-serine and its effects on NMDAR synaptic plasticity. SIGNIFICANCE STATEMENT Despite the plethora of roles attributed to D-serine, the regulation of its synaptic turnover is poorly understood. We identified the system A transporters Slc38a1 and Slc38a2 as the main pathway for neuronal reuptake of D-serine. These transporters are not saturated with glutamine in vivo and provide an unexpected link between the serine shuttle pathway, responsible for regulating D-serine synaptic turnover, and the glutamine–glutamate cycle. Our observations suggest that Slc38a1 and Slc38a2 have a dual role in regulating neurotransmission. In addition to their classical role as the glutamine providers, the system A transporters regulate extracellular D-serine and therefore affect NMDAR-dependent synaptic plasticity. Higher glutamine export from astrocytes would increase extracellular D-serine, providing a feedforward mechanism to increase synaptic NMDAR activation.
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d-Serine crosses the blood-brain barrier by amino acid transporter solute carrier family 6 member 14.
“d-Serine serves as a neuromodulator and crosses the BBB by amino acid transporter solute carrier family 6 member 14 (refs. 31–35).”
From Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system (2025) · cites this paper as [33]
The Introduction describes D-serine’s role in synaptic signaling, but does not discuss its passage across the blood–brain barrier. Searches for SLC6A14 and blood–brain barrier transport found no passage establishing the claimed route; the References instead list D-serine transport in the colon and a blood–brain barrier transporter for glutamine. (LLM, conf=0.77)
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NMDARs, Coincidence Detectors of Astrocytic and Neuronal Activities
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Aging-Associated Cognitive Decline is Reversed by D-Serine Supplementation
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Serine Racemase Deletion Affects the Excitatory/Inhibitory Balance of the Hippocampal CA1 Network
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Excitotoxic Storms of Ischemic Stroke: A Non-neuronal Perspective
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DTD1 modulates synaptic efficacy by maintaining D-serine and D-aspartate homeostasis
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D-Serine in the Treatment of Psychosis
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Mammalian Tolerance to Amino Acid Heterochirality
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Self-citation
- Authors
- Bodner, O., Radzishevsky, I., Foltyn, V. N., Touitou, A., Valenta, A. C., Rangel, I. F., Panizzutti, R., Kennedy, R. T., Billard, J. M., & Wolosker, H.
- Affiliations
- Technion – Israel Institute of Technology (IL)
- University of Michigan (US)
- Universidade Federal do Rio de Janeiro (BR)
- Inserm (FR)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2020-07-13
- Volume
- 40
- Issue
- 34
- Pages
- 6489-6502
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC7486657
- OpenAlex
- W3042065120
- Cited by
- 49
- References
- 81
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 5 · 2023: 8 · 2022: 8 · 2021: 6 · 2020: 5
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Université de Caen Normandie
- National Institutes of Health
- National Institute of Biomedical Imaging and Bioengineering (R01EB003320)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- D-serine, NMDA receptor, synaptic plasticity, SLC38A1, SLC38A2, glutamine, long-term potentiation, Schaffer collateral-CA1 synapses, serine racemase, sex differences
- MeSH terms
- Animals, Female, Glutamine, Hippocampus, Male, Mice, Inbred C57BL, Mice, Transgenic, Synaptic Transmission, Neuronal Plasticity, Serine, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Amino Acid Transport System A
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