| Title: |
The NMDA receptor activation by d -serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle |
| Authors: |
Neame, Samah; Safory, Hazem; Radzishevsky, Inna; Touitou, Ayelet; Marchesani, Francesco; Marchetti, Marialaura; Kellner, Shai; Berlin, Shai; Foltyn, Veronika, N; Engelender, Simone; Billard, Jean-Marie; Wolosker, Herman |
| Contributors: |
Technion - Israel Institute of Technology Haifa; Università degli studi di Parma = University of Parma (UNIPR); Mobilités : Vieillissement, Pathologie, Santé (COMETE); Université de Caen Normandie (UNICAEN); Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Source: |
ISSN: 0027-8424. |
| Publisher Information: |
CCSD; National Academy of Sciences |
| Publication Year: |
2019 |
| Collection: |
Normandie Université: HAL |
| Subject Terms: |
Phgdh; d-serine; gliotransmission; glycine; tripartite synapse; [SDV]Life Sciences [q-bio] |
| Description: |
International audience ; Astrocytes express the 3-phosphoglycerate dehydrogenase (Phgdh) enzyme required for the synthesis of L-serine from glucose. Astro- cytic L-serine was proposed to regulate NMDAR activity by shuttling to neurons to sustain D-serine production, but this hypothesis re- mains 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 pre- dominant 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 con- sists of tonic inhibition of SR by intracellular glycine observed in vitro, primary cultures, and in vivo microdialysis. The second in- volves 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/31548413; PUBMED: 31548413; PUBMEDCENTRAL: PMC6789919 |
| DOI: |
10.1073/pnas.1909458116 |
| Availability: |
https://hal.science/hal-04688152; https://hal.science/hal-04688152v1/document; https://hal.science/hal-04688152v1/file/PNAS%202019.pdf; https://doi.org/10.1073/pnas.1909458116 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.2B5F70CC |
| Database: |
BASE |