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@ARTICLE{Kambali:276799,
author = {Kambali, Maltesh and Li, Yan and Unichenko, Petr and Feria
Pliego, Jessica A and Yadav, Rachita and Liu, Jing and
McGuinness, Patrick and Cobb, Johanna G and Wang, Muxiao and
Nagarajan, Rajasekar and Lyu, Jinrui and Vongsouthi, Vanessa
and Jackson, Colin J and Engin, Elif and Coyle, Joseph T and
Shin, Jaeweon and Hodgson, Nathaniel W and Hensch, Takao K
and Talkowski, Michael E and Homanics, Gregg E and
Bolshakov, Vadim Y and Henneberger, Christian and Rudolph,
Uwe},
title = {{A}n increased copy number of glycine decarboxylase
({GLDC}) associated with psychosis reduces extracellular
glycine and impairs {NMDA} receptor function.},
journal = {Molecular psychiatry},
volume = {30},
number = {3},
issn = {1359-4184},
address = {[London]},
publisher = {Springer Nature},
reportid = {DZNE-2025-00324},
pages = {927 - 942},
year = {2025},
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.},
keywords = {Animals / Glycine Dehydrogenase (Decarboxylating):
metabolism / Glycine Dehydrogenase (Decarboxylating):
genetics / Mice / Glycine: metabolism / Receptors,
N-Methyl-D-Aspartate: metabolism / Receptors,
N-Methyl-D-Aspartate: genetics / Dentate Gyrus: metabolism /
Long-Term Potentiation: genetics / Psychotic Disorders:
metabolism / Psychotic Disorders: genetics / Male /
Schizophrenia: metabolism / Schizophrenia: genetics / Humans
/ Mice, Inbred C57BL / Synapses: metabolism / Neuronal
Plasticity: physiology / Glycine Dehydrogenase
(Decarboxylating) (NLM Chemicals) / Glycine (NLM Chemicals)
/ Receptors, N-Methyl-D-Aspartate (NLM Chemicals)},
cin = {AG Henneberger},
ddc = {610},
cid = {I:(DE-2719)1013029},
pnm = {351 - Brain Function (POF4-351)},
pid = {G:(DE-HGF)POF4-351},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39210012},
doi = {10.1038/s41380-024-02711-5},
url = {https://pub.dzne.de/record/276799},
}