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Serine Racemase Expression by Striatal Neurons

Abstract

d-serine is synthesized by serine racemase (SR) and is a co-agonist at forebrain N-methyl-d-aspartate receptors (NMDARs). d-serine and SR are expressed primarily in neurons, but not in quiescent astrocytes. In this study, we examined the localization of d-serine and SR in the mouse striatum and the effects of genetically silencing SR expression in GABAergic interneurons (iSR−/−). iSR−/− mice had substantially reduced SR expression almost exclusively in striatum, but only exhibited marginal d-serine reduction. SR positive cells in the striatum showed strong co-localization with dopamine- and cyclic AMP-regulated neuronal phosphoprotein (DARPP32) in wild type mice. Transgenic fluorescent reporter mice for either the D1 or D2 dopamine receptors exhibited a 65:35 ratio for co-localization with D1and D2 receptor positive cells, respectively. These results indicate that GABAergic medium spiny neurons receiving dopaminergic inputs in striatum robustly and uniformly express SR. In behavioral tests, iSR−/− mice showed a blunted response to the hedonic and stimulant effects of cocaine, without affecting anxiety-related behaviors. Because the cocaine effects have been shown in the constitutive SR−/− mice, the restriction of the blunted response to cocaine to iSR−/− mice reinforces the conclusion that d-serine in striatal GABAergic neurons plays an important role in mediating dopaminergic stimulant effects. Results in this study suggest that SR in striatal GABAergic neurons is synthesizing d-serine, not as a glutamatergic co-transmitter, but rather as an autocrine whereby the GABAergic neurons control the excitability of their NMDARs by determining the availability of the co-agonist, d-serine.

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Acknowledgements

We thank Dr. Toru Nishikawa and Dr. Makoto Taniguchi for advice and support, as well as Alexandra Berg and Kendall Presti for animal colony maintenance and genotyping. This research was supported by A Phyllis and Jerome Lyle Rappaport Mental Health Research Scholars Award, 1K99MH099252-01A1, and 5R00MH099252-04 (DTB); R01MH05190 and P50MH0G0450 (JTC). Shunsuke Takagi was supported in part by Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation from the Japan Society for the Promotion of Science (S2301). Since participating in this study, MDP has taken a position at Alkermes.

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Contributions

ST and JTC designed the study. DTB and JTC contributed to analysis and interpretation of data and assisted in the preparation of the manuscript. MDP and TA contributed to the histochemical studies and animal behavior testing. All authors had contributed to data collection and interpretation, and critically reviewed the manuscript. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Joseph T. Coyle.

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Conflict of interest

JTC reports consulting with Concert Pharm and holding a Patent on d-serine for the Treatment of Serious Mental Illness, which is owned by Massachusetts General Hospital. MDP is currently employed by Alkermes Pharm. DTB served as a Consultant for LifeSci Capital and received research support from Takeda Pharmaceuticals. ST and TA report no conflicts of interest.

Ethical Approval

All animal procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (National Academy of Sciences, 2011) and were approved by the McLean Hospital Institutional Animal Care and Use Committee.

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Takagi, S., Puhl, M.D., Anderson, T. et al. Serine Racemase Expression by Striatal Neurons. Cell Mol Neurobiol 42, 279–289 (2022). https://doi.org/10.1007/s10571-020-00880-9

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  • DOI: https://doi.org/10.1007/s10571-020-00880-9

Keywords

  • d-serine
  • d-amino acid oxidase
  • Glutamic acid decarboxylase
  • Gamma-aminobutyric acid
  • N-methyl-d-aspartic acid
  • Serine racemase