Kambali, MalteshLi, YanUnichenko, PetrFeria Pliego, Jessica A.Yadav, RachitaLiu, JingMcGuinness, PatrickCobb, Johanna G.Wang, MuxiaoNagarajan, RajasekarLyu, JinruiVongsouthi, VanessaJackson, Colin J.Engin, ElifCoyle, Joseph T.Shin, JaeweonHodgson, Nathaniel W.Hensch, Takao K.Talkowski, Michael E.Homanics, Gregg E.Bolshakov, Vadim Y.Henneberger, ChristianRudolph, Uwe2025-05-232025-05-231359-4184PubMed:39210012ORCID:/0000-0001-6150-3822/work/184102724WOS:001303212300001http://www.scopus.com/inward/record.url?scp=85202642724&partnerID=8YFLogxKhttps://hdl.handle.net/1885/733752896Glycine 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.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.16en© 2024 The Author(s)202410.1038/s41380-024-02711-585202642724