Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function.

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.

https://www.pnas.org/content/pnas/116/41/20736.full.pdf

The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle

Summary Astrocytes influence neuronal maturation and function by providing trophic support, regulating the extracellular environment, and modulating signaling at synapses. The emergence of induced pluripotent stem cell (iPSC) technology offers a human system with which to validate and re-evaluate insights from animal studies. Here, we set out to examine interactions between human astrocytes and neurons derived from a common cortical progenitor pool, thereby recapitulating aspects of in vivo cortical development. We show that the cortical iPSC-derived astrocytes exhibit many of the molecular and functional hallmarks of astrocytes. Furthermore, optogenetic and electrophysiological co-culture experiments reveal that the iPSC-astrocytes can actively modulate ongoing synaptic transmission and exert pro-maturational effects upon developing networks of iPSC-derived cortical neurons. Finally, transcriptomic analyses implicate synapse-associated extracellular signaling in the astrocytes' pro-maturational effects upon the iPSC-derived neurons. This work helps lay the foundation for future investigations into astrocyte-to-neuron interactions in human health and disease.

Pro-maturational Effects of Human iPSC-Derived Cortical Astrocytes upon iPSC-Derived Cortical Neurons.

Serine metabolism antagonizes antiviral innate immunity by preventing ATP6V0d2-mediated YAP lysosomal degradation

Astrocytes are the most abundant cells in the brain. They have many important functions in the central nervous system (CNS), including the maintenance of glutamate and ion homeostasis, the elimination of oxidative stress, energy storage in glycogen, tissue repair, regulating synaptic activity by releasing neurotransmitters, and participating in synaptic formation. Astrocytes have special highly ramified structure. Their branches contact with synapses of neurons inwardly, with fine structure and wrapping synapses; their feet contact with blood vessels of brain parenchyma outward, almost wrapping the whole brain. The adjacent astrocytes rarely overlap and communicate with each other through gap junction channels. The ideal location of astrocytes enables them to sense the weak changes of their surroundings and provide the structural basis for the energy supply of neurons. Neurons and astrocytes are closely coupled units of energy metabolism in the brain. Neurons consume a lot of ATPs in the process of neurotransmission. Astrocytes provide metabolic substrates for neurons, maintain high activity of neuron, and facilitate information transmission of neurons. This article reviews the characteristics of glucose metabolism, lipid metabolism, and amino acid metabolism of astrocytes. The metabolic interactions between astrocytes and neurons, astrocytes and microglia were also detailed discussed. Finally, we classified analyzed the role of metabolic disorder of astrocytes in the occurrence and development of neurodegenerative diseases.

Brain Energy Metabolism: Astrocytes in Neurodegenerative Diseases

d-serine is a physiologic coagonist of NMDA receptors, but little is known about the regulation of its synthesis and synaptic turnover The amino acid exchangers ASCT1 (Slc1a4) and ASCT2 (Slc1a5) are candidates for regulating d-serine levels Using ASCT1 and ASCT2 KO mice, we report that ASCT1, rather than ASCT2, is a physiologic regulator of d-serine metabolism ASCT1 is a major d-serine uptake system in astrocytes and can also export l-serine via heteroexchange, supplying neurons with the substrate for d-serine synthesis ASCT1-KO mice display lower levels of brain d-serine along with higher levels of l-alanine, l-threonine, and glycine Deletion of ASCT1 was associated with neurodevelopmental alterations including lower hippocampal and striatal volumes and changes in the expression of neurodevelopmental-relevant genes Furthermore, ASCT1-KO mice exhibited deficits in motor function, spatial learning, and affective behavior, along with changes in the relative contributions of d-serine vs glycine in mediating NMDA receptor activity In vivo microdialysis demonstrated lower levels of extracellular d-serine in ASCT1-KO mice, confirming altered d-serine metabolism These alterations are reminiscent of some of the neurodevelopmental phenotypes exhibited by patients with ASCT1 mutations ASCT1-KO mice provide a useful model for potential therapeutic interventions aimed at correcting the metabolic impairments in patients with ASCT1 mutations

https://www.pnas.org/content/pnas/115/38/9628.full.pdf

ASCT1 (Slc1a4) transporter is a physiologic regulator of brain d-serine and neurodevelopment.

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.

D-Serine Signaling and NMDAR-Mediated Synaptic Plasticity Are Regulated by System A-Type of Glutamine/D-Serine Dual Transporters.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(16)00112-4.pdf

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ASCT1 (Slc1a4) transporter is a physiologic regulator of brain d-serine and neurodevelopment.

D-Serine Signaling and NMDAR-Mediated Synaptic Plasticity Are Regulated by System A-Type of Glutamine/D-Serine Dual Transporters.

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