The NMDA receptor activation by d -serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle
| Autor: | Marialaura Marchetti, Hazem Safory, Shai Kellner, Simone Engelender, Shai Berlin, Inna Radzishevsky, Veronika N. Foltyn, Samah Neame, Francesco Marchesani, Ayelet Touitou, Jean-Marie Billard, Herman Wolosker |
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| Přispěvatelé: | Rappaport faculty of Medicine, Technion - Israel Institute of Technology [Haifa], University of Parma = Università degli studi di Parma [Parme, Italie], Mobilités : Vieillissement, Pathologie, Santé (COMETE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU) |
| Rok vydání: | 2019 |
| Předmět: |
Long-Term Potentiation
Glycine Racemases and Epimerases Hippocampus Receptors N-Methyl-D-Aspartate Serine Synapse Mice 03 medical and health sciences 0302 clinical medicine Tripartite synapse Animals ComputingMilieux_MISCELLANEOUS Phosphoglycerate Dehydrogenase 030304 developmental biology Mice Knockout Neurons 0303 health sciences Multidisciplinary Glycine cleavage system Chemistry Long-term potentiation Biological Sciences Cell biology Mice Inbred C57BL nervous system Astrocytes Serine racemase Synapses NMDA receptor [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] 030217 neurology & neurosurgery |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2019, 116 (41), pp.20736-20742. ⟨10.1073/pnas.1909458116⟩ |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1909458116 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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