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An increased copy number of glycine decarboxylase (GLDC) associated with psychosis reduces extracellular glycine and impairs NMDA receptor function.
Kambali, Maltesh; Li, Yan; Unichenko, Petr; Feria Pliego, Jessica A; Yadav, Rachita; Liu, Jing; McGuinness, Patrick; Cobb, Johanna G; Wang, Muxiao; Nagarajan, Rajasekar; Lyu, Jinrui; Vongsouthi, Vanessa; Jackson, Colin J; Engin, Elif; Coyle, Joseph T; Shin, Jaeweon; Hodgson, Nathaniel W; Hensch, Takao K; Talkowski, Michael E; Homanics, Gregg E; Bolshakov, Vadim Y; Henneberger, Christian; Rudolph, Uwe.
Afiliación
  • Kambali M; Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • Li Y; Cellular Neurobiology Laboratory, McLean Hospital Belmont, Belmont, MA, USA.
  • Unichenko P; Deparment of Psychiatry, Harvard Medical School, Boston, MA, USA.
  • Feria Pliego JA; Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Bonn, Germany.
  • Yadav R; Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Bonn, Germany.
  • Liu J; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • McGuinness P; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Cobb JG; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Wang M; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Nagarajan R; Deparment of Psychiatry, Harvard Medical School, Boston, MA, USA.
  • Lyu J; Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, USA.
  • Vongsouthi V; Deparment of Psychiatry, Harvard Medical School, Boston, MA, USA.
  • Jackson CJ; Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, USA.
  • Engin E; Deparment of Psychiatry, Harvard Medical School, Boston, MA, USA.
  • Coyle JT; Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, USA.
  • Shin J; Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • Hodgson NW; Neuroscience Program, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • Hensch TK; Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • Talkowski ME; Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • Homanics GE; Neuroscience Program, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • Bolshakov VY; Research School of Chemistry, Australian National University, Canberra, ACT, Australia.
  • Henneberger C; Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Australian National University, Canberra, ACT, 2601, Australia.
  • Rudolph U; Research School of Chemistry, Australian National University, Canberra, ACT, Australia.
Mol Psychiatry ; 2024 Aug 30.
Article en En | MEDLINE | ID: mdl-39210012
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Psychiatry Asunto de la revista: BIOLOGIA MOLECULAR / PSIQUIATRIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Psychiatry Asunto de la revista: BIOLOGIA MOLECULAR / PSIQUIATRIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido