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000276799 1001_ $$aKambali, Maltesh$$b0
000276799 245__ $$aAn increased copy number of glycine decarboxylase (GLDC) associated with psychosis reduces extracellular glycine and impairs NMDA receptor function.
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000276799 520__ $$aGlycine 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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000276799 650_7 $$0EC 1.4.4.2$$2NLM Chemicals$$aGlycine Dehydrogenase (Decarboxylating)
000276799 650_7 $$0TE7660XO1C$$2NLM Chemicals$$aGlycine
000276799 650_7 $$2NLM Chemicals$$aReceptors, N-Methyl-D-Aspartate
000276799 650_2 $$2MeSH$$aAnimals
000276799 650_2 $$2MeSH$$aGlycine Dehydrogenase (Decarboxylating): metabolism
000276799 650_2 $$2MeSH$$aGlycine Dehydrogenase (Decarboxylating): genetics
000276799 650_2 $$2MeSH$$aMice
000276799 650_2 $$2MeSH$$aGlycine: metabolism
000276799 650_2 $$2MeSH$$aReceptors, N-Methyl-D-Aspartate: metabolism
000276799 650_2 $$2MeSH$$aReceptors, N-Methyl-D-Aspartate: genetics
000276799 650_2 $$2MeSH$$aDentate Gyrus: metabolism
000276799 650_2 $$2MeSH$$aLong-Term Potentiation: genetics
000276799 650_2 $$2MeSH$$aPsychotic Disorders: metabolism
000276799 650_2 $$2MeSH$$aPsychotic Disorders: genetics
000276799 650_2 $$2MeSH$$aMale
000276799 650_2 $$2MeSH$$aSchizophrenia: metabolism
000276799 650_2 $$2MeSH$$aSchizophrenia: genetics
000276799 650_2 $$2MeSH$$aHumans
000276799 650_2 $$2MeSH$$aMice, Inbred C57BL
000276799 650_2 $$2MeSH$$aSynapses: metabolism
000276799 650_2 $$2MeSH$$aNeuronal Plasticity: physiology
000276799 7001_ $$00000-0003-3673-181X$$aLi, Yan$$b1
000276799 7001_ $$aUnichenko, Petr$$b2
000276799 7001_ $$00000-0001-9766-613X$$aFeria Pliego, Jessica A$$b3
000276799 7001_ $$aYadav, Rachita$$b4
000276799 7001_ $$aLiu, Jing$$b5
000276799 7001_ $$aMcGuinness, Patrick$$b6
000276799 7001_ $$aCobb, Johanna G$$b7
000276799 7001_ $$00000-0002-3021-4929$$aWang, Muxiao$$b8
000276799 7001_ $$aNagarajan, Rajasekar$$b9
000276799 7001_ $$aLyu, Jinrui$$b10
000276799 7001_ $$aVongsouthi, Vanessa$$b11
000276799 7001_ $$00000-0001-6150-3822$$aJackson, Colin J$$b12
000276799 7001_ $$00000-0002-1804-6811$$aEngin, Elif$$b13
000276799 7001_ $$aCoyle, Joseph T$$b14
000276799 7001_ $$aShin, Jaeweon$$b15
000276799 7001_ $$aHodgson, Nathaniel W$$b16
000276799 7001_ $$00000-0003-0748-8152$$aHensch, Takao K$$b17
000276799 7001_ $$00000-0003-2889-0992$$aTalkowski, Michael E$$b18
000276799 7001_ $$00000-0003-3641-8153$$aHomanics, Gregg E$$b19
000276799 7001_ $$00000-0002-4639-3482$$aBolshakov, Vadim Y$$b20
000276799 7001_ $$0P:(DE-2719)2811625$$aHenneberger, Christian$$b21
000276799 7001_ $$00000-0001-9396-4746$$aRudolph, Uwe$$b22
000276799 773__ $$0PERI:(DE-600)1502531-7$$a10.1038/s41380-024-02711-5$$gVol. 30, no. 3, p. 927 - 942$$n3$$p927 - 942$$tMolecular psychiatry$$v30$$x1359-4184$$y2025
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