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An increased copy number of glycine decarboxylase (GLDC) associated with psychosis reduces extracellular glycine and impairs NMDA receptor function

Molecular Psychiatry volume 30, pages 927–942 (2025)Cite this article

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Abstract

Glycine is an obligatory co-agonist at excitatory NMDA receptors in the brain, especially in the dentate gyrus, which has been postulated to be crucial for the development of psychotic associations and memories with psychotic content. Drugs modulating glycine levels are in clinical development for improving cognition in schizophrenia. However, the functional relevance of the regulation of glycine metabolism by endogenous enzymes is unclear. Using a chromosome-engineered allelic series in mice, we report that a triplication of the gene encoding the glycine-catabolizing enzyme glycine decarboxylase (GLDC) - as found on a small supernumerary marker chromosome in patients with psychosis - reduces extracellular glycine levels as determined by optical fluorescence resonance energy transfer (FRET) in dentate gyrus (DG) and suppresses long-term potentiation (LTP) in mPP-DG synapses but not in CA3-CA1 synapses, reduces the activity of biochemical pathways implicated in schizophrenia and mitochondrial bioenergetics, and displays deficits in schizophrenia-like behaviors which are in part known to be dependent on the activity of the dentate gyrus, e.g., prepulse inhibition, startle habituation, latent inhibition, working memory, sociability and social preference. Our results demonstrate that Gldc negatively regulates long-term synaptic plasticity in the dentate gyrus in mice, suggesting that an increase in GLDC copy number possibly contributes to the development of psychosis in humans.

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Fig. 1: Schematic representation of the generation of the 9p24.1 CNV mice.
Fig. 2: Gene expression changes in hippocampal and prefrontal cortex with KEGG enrichment pathways, and associated enrichment with TADA-ASD and NDD gene sets.
Fig. 3: Generation and characterization of shorter complementary CNVs from the 9p24.1 CNV (9LR) using CRISPR/Cas-9 genome editing.
Fig. 4: Akt/mTOR signaling and expression of BDNF in synaptoneurosomal fractions prepared from whole hippocampus in 4c9R mice.
Fig. 5: Effect of 4 copies of Gldc on dendritic spine morphology, mitochondrial bioenergetics and histone methylation in dentate gyrus and CA1.
Fig. 6: Effect of Gldc copy number variation on startle habituation, latent inhibition, prepulse inhibition and working memory.

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Data availability

RNA sequencing dataare available in the supplementary material and have been deposited in the NCBI GEO database with the following accession number: GSE230871. Other primary data will be archived in the Harvard Dataverse Repository.

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Acknowledgements

UR thanks Dr. Bruce M. Cohen, McLean Hospital and Harvard Medical School, and Dr. Edward M. Scolnick, Broad Institute of Harvard and MIT, for their encouragement and support, and for providing seed funding from the Shervert Frazier Research Institute at McLean Hospital and the Stanley Center for Psychiatric Research at the Broad Institute, respectively, Dr. Herman Wolosker (Technion-Israel Institute of Technology) for helpful discussions, and Kelly Brown (McLean Hospital) for performing water T maze experiments. We thank Drs. Xinzhu Yu, Wenyan Mei and Makoto Inoue (UIUC) for providing antibodies for immunofluorescence. Research in this paper was further supported by a Harvard Brain Science Initiative Bipolar Disorder Seed Grant, supported by Kent and Liz Dauten, to UR and VYB, and by the National Institute of Mental Health of the National Institutes of Health under award numbers R21MH104505 and R56MH112642 to UR, R01MH115957, R01HD096326, R01MH123155, and R01NS093200 to MET and RY, P50MH115874; R01MH123993; and R01MH108665 to VYB, R01MH051290 to JTC, P50MH094271 to TKH, and U01AA020889 to GEH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This paper is dedicated to the memory of Dr. Deborah L. Levy (1950–2020), psychologist and researcher at McLean Hospital and Harvard Medical School, who conducted family studies that were essential for the identification and characterization of the marker chromosome in the two patients and who had a crucial role in initiating the studies reported here.

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Authors and Affiliations

  1. Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL, USA

    Maltesh Kambali, Muxiao Wang, Rajasekar Nagarajan, Jinrui Lyu & Uwe Rudolph

  2. Cellular Neurobiology Laboratory, McLean Hospital Belmont, Belmont, MA, USA

    Yan Li & Vadim Y. Bolshakov

  3. Deparment of Psychiatry, Harvard Medical School, Boston, MA, USA

    Yan Li, Jing Liu, Patrick McGuinness, Johanna G. Cobb, Elif Engin, Joseph T. Coyle, Vadim Y. Bolshakov & Uwe Rudolph

  4. Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Bonn, Germany

    Petr Unichenko, Jessica A. Feria Pliego & Christian Henneberger

  5. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Rachita Yadav, Jaeweon Shin & Michael E. Talkowski

  6. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Rachita Yadav & Michael E. Talkowski

  7. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Rachita Yadav & Michael E. Talkowski

  8. Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Rachita Yadav & Michael E. Talkowski

  9. Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, USA

    Jing Liu, Patrick McGuinness, Johanna G. Cobb, Elif Engin & Uwe Rudolph

  10. Neuroscience Program, University of Illinois Urbana-Champaign, Urbana, IL, USA

    Muxiao Wang, Jinrui Lyu & Uwe Rudolph

  11. Research School of Chemistry, Australian National University, Canberra, ACT, Australia

    Vanessa Vongsouthi & Colin J. Jackson

  12. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Australian National University, Canberra, ACT, 2601, Australia

    Vanessa Vongsouthi & Colin J. Jackson

  13. F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA

    Nathaniel W. Hodgson & Takao K. Hensch

  14. Center for Brain Science, Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA

    Nathaniel W. Hodgson & Takao K. Hensch

  15. Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Gregg E. Homanics

  16. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

    Christian Henneberger

  17. Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Champaign, IL, USA

    Uwe Rudolph

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  1. Maltesh Kambali
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  2. Yan Li
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  23. Uwe Rudolph
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Contributions

This study was conceived, designed and supervised by UR. Generation of genetically modified mouse models by J. Liu, JGC, EE, and GEH. PM performed and analyzed the molecular and behavioral assessment of the full CNVs. MK performed and analyzed experiments for partial complementary CNVs. MK performed and analyzed molecular experiments, immunofluorescence, GLDC enzyme activity assay, neuronal morphological and spine density analysis. MK and MW performed and analyzed mitochondrial bioenergetics assay. MK performed various behavioral experiments and analysis. NWH and TKH performed and analyzed thiol measurements with HPLC. YL and VYB performed and analyzed electrophysiological experiments. PU, JAFP and CH performed and analyzed extracellular glycine measurements. RY, JS and MET performed and analyzed RNA sequencing experiments. VV and CJJ provided GlyFS. RN and J. Lyu analyzed experiments. MK prepared graphs for molecular and behavioral analysis of the full CNVs and graphs for RNAseq results. MK prepared figures. MK, VYB, CH and UR wrote the manuscript. All authors revised and approved the final version of the manuscript. Authors who performed and oversaw statistical analysis: MK, YL, PU, JAFP, RY, PM, JS, NWH, TKH, MET, VYB, CH, UR. Authors who had unrestricted access to all data: MK, UR. Authors who prepared the first draft of the manuscript reviewed, and edited it: MK, UR. All authors agreed to submit the manuscript, read and approved the final draft and take full responsibility of its content, including the accuracy of the data and the statistical analysis.

Corresponding author

Correspondence to Uwe Rudolph.

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Competing interests

UR serves on the Scientific Advisory Board of Damona Pharmaceuticals. The other authors report no competing interests.

Ethics approval

All methods were performed in accordance with the relevant guidelines and regulations. All animal experiments and procedures were approved by the Institutional Animal Care and Use Committees of McLean Hospital (10-2/2-2, 10-2/2-3, 13-3/2-8, 13-3/2-9, 2014N000182, 2016N000041, 2016N000044, 2017N000125, and 2018N00074), the University of Illinois Urbana-Champaign (18206, 18207, 21222, 22005), and the University of Pittsburgh (14104910).

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Kambali, M., Li, Y., Unichenko, P. et al. An increased copy number of glycine decarboxylase (GLDC) associated with psychosis reduces extracellular glycine and impairs NMDA receptor function. Mol Psychiatry 30, 927–942 (2025). https://doi.org/10.1038/s41380-024-02711-5

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