Journal Article

DZNE-2025-00324

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png An increased copy number of glycine decarboxylase (GLDC) associated with psychosis reduces extracellular glycine and impairs NMDA receptor function.

Kambali, M. ; Li, Y. ; Unichenko, P. ; Feria Pliego, J. A. ; Yadav, R. ; Liu, J. ; McGuinness, P. ; Cobb, J. G. ; Wang, M. ; Nagarajan, R. ; Lyu, J. ; Vongsouthi, V. ; Jackson, C. J. ; Engin, E. ; Coyle, J. T. ; Shin, J. ; Hodgson, N. W. ; Hensch, T. K. ; Talkowski, M. E. ; Homanics, G. E. ; Bolshakov, V. Y. ; Henneberger, C.DZNE* ; Rudolph, U.

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41380-024-02711-5

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.

Keyword(s): Animals (MeSH) ; Glycine Dehydrogenase (Decarboxylating): metabolism (MeSH) ; Glycine Dehydrogenase (Decarboxylating): genetics (MeSH) ; Mice (MeSH) ; Glycine: metabolism (MeSH) ; Receptors, N-Methyl-D-Aspartate: metabolism (MeSH) ; Receptors, N-Methyl-D-Aspartate: genetics (MeSH) ; Dentate Gyrus: metabolism (MeSH) ; Long-Term Potentiation: genetics (MeSH) ; Psychotic Disorders: metabolism (MeSH) ; Psychotic Disorders: genetics (MeSH) ; Male (MeSH) ; Schizophrenia: metabolism (MeSH) ; Schizophrenia: genetics (MeSH) ; Humans (MeSH) ; Mice, Inbred C57BL (MeSH) ; Synapses: metabolism (MeSH) ; Neuronal Plasticity: physiology (MeSH) ; Glycine Dehydrogenase (Decarboxylating) ; Glycine ; Receptors, N-Methyl-D-Aspartate

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Contributing Institute(s):

1. Synaptic and Glial Plasticity (AG Henneberger)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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