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.

甘氨酸是大脑中兴奋性 NMDA 受体的强制性共激动剂，尤其是在齿状回中，据推测，这对于精神病关联和与精神病内容的记忆的发展至关重要。调节甘氨酸水平的药物正在临床开发中，以改善精神分裂症的认知能力。然而，内源性酶调节甘氨酸代谢的功能相关性尚不清楚。在小鼠中使用染色体工程等位基因系列，我们报道了编码甘氨酸分解代谢酶甘氨酸脱羧酶 （GLDC） 的基因的一式三份 - 如在精神病患者的小多余标记染色体上发现的那样 - 降低细胞外甘氨酸水平，由齿状回 （DG） 中的光学荧光共振能量转移 （FRET） 确定，并抑制 mPP-DG 突触中的长时程增强 （LTP），但不抑制 CA3-CA1 突触中， 降低与精神分裂症和线粒体生物能量学有关的生化途径的活性，并显示精神分裂症样行为的缺陷，这些行为部分已知取决于齿状回的活动，例如，前脉冲抑制，惊吓习惯，潜在抑制，工作记忆，社交性和社会偏好。我们的结果表明，Gldc 负向调节小鼠齿状回的长期突触可塑性，表明 GLDC 拷贝数的增加可能有助于人类精神病的发展。