TY - JOUR
T1 - An increased copy number of glycine decarboxylase (GLDC) associated with psychosis reduces extracellular glycine and impairs NMDA receptor function
AU - Kambali, Maltesh
AU - Li, Yan
AU - Unichenko, Petr
AU - Feria Pliego, Jessica A.
AU - Yadav, Rachita
AU - Liu, Jing
AU - McGuinness, Patrick
AU - Cobb, Johanna G.
AU - Wang, Muxiao
AU - Nagarajan, Rajasekar
AU - Lyu, Jinrui
AU - Vongsouthi, Vanessa
AU - Jackson, Colin J.
AU - Engin, Elif
AU - Coyle, Joseph T.
AU - Shin, Jaeweon
AU - Hodgson, Nathaniel W.
AU - Hensch, Takao K.
AU - Talkowski, Michael E.
AU - Homanics, Gregg E.
AU - Bolshakov, Vadim Y.
AU - Henneberger, Christian
AU - Rudolph, Uwe
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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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U2 - 10.1038/s41380-024-02711-5
DO - 10.1038/s41380-024-02711-5
M3 - Article
C2 - 39210012
AN - SCOPUS:85202642724
SN - 1359-4184
JO - Molecular Psychiatry
JF - Molecular Psychiatry
ER -