An increased copy number of glycine decarboxylase (GLDC) associated with psychosis reduces extracellular glycine and impairs NMDA receptor function.

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.

A marker chromosome in psychosis identifies glycine decarboxylase (GLDC) as a novel regulator of neuronal and synaptic function in the hippocampus.

The biological significance of a small supernumerary marker chromosome that results in dosage alterations to chromosome 9p24.1, including triplication of the GLDC gene encoding glycine decarboxylase, in two patients with psychosis is unclear. In an allelic series of copy number variant mouse models, we identify that triplication of Gldc reduces extracellular glycine levels as determined by optical fluorescence resonance energy transfer (FRET) in dentate gyrus (DG) but not in CA1, 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 prepulse inhibition, startle habituation, latent inhibition, working memory, sociability and social preference. Our results thus provide a link between a genomic copy number variation, biochemical, cellular and behavioral phenotypes, and further demonstrate that GLDC negatively regulates long-term synaptic plasticity at specific hippocampal synapses, possibly contributing to the development of neuropsychiatric disorders.

A Retrospective Study of Acute Postoperative Pain After Cesarean Delivery in Patients With Opioid Use Disorder Treated With Opioid Agonist Pharmacotherapy.

OBJECTIVE: We aimed to quantify the effect of opioid agonist pharmacotherapy on pain management after cesarean delivery, compared with patients not on these medications. METHODS: Patients undergoing cesarean delivery at our institution between January 2016 and December 2018 were stratified by peripartum use of opioid agonist pharmacotherapy versus no agonist therapy. We compared 24-hour postoperative opioid consumption not including buprenorphine and methadone, in milligram morphine equivalents (MME) (primary outcome), highest pain score on a 0 to 10 numerical rating scale in the first 24 postoperative hours, and postoperative length of stay in hours (secondary outcomes) between groups. These outcomes were also compared after covariate adjustment using logistic regression. RESULTS: We identified 123 patients on opioid agonist pharmacotherapy - in the form of buprenorphine or methadone and 2856 patients not on these medications. The groups differed in demographic characteristics, including age, smoking, and marital status. Opioid consumption during the first 24 postoperative hours (median [interquartile range]) was 99 [75,120] MME for patients on agonist therapy and 30 [0, 64] MME among parturients not taking these medications ( P < 0.001). Highest pain scores during this time were also higher for patients on opioid agonist pharmacotherapy (mean [standard deviation]: 8.2 [1.6] vs 5.5 [2.2], P < 0.001 for the no agonist group). Postoperative length of stay was 73 [68, 77] hours for patients on agonist pharmacotherapy, and 71 [62, 76] hours for parturients taking no agonist ( P < 0.001). All differences remained significant after covariate adjustment. CONCLUSIONS: Parturients on opioid agonist pharmacotherapy have markedly increased opioid utilization and pain severity after cesarean delivery.

Astrocytes in primary cultures express serine racemase, synthesize d-serine and acquire A1 reactive astrocyte features.

d-Serine is a co-agonist at forebrain N-methyl-d-aspartate receptors (NMDAR) and is synthesized by serine racemase (SR). Although d-serine and SR were originally reported to be localized to glia, recent studies have provided compelling evidence that under healthy physiologic conditions both are localized primarily in neurons. However, in pathologic conditions, reactive astrocytes can also express SR and synthesize d-serine. Since cultured astrocytes exhibit features of reactive astrocytes, we have characterized d-serine synthesis and the expression of enzymes involved in its disposition in primary glial cultures. The levels of SR were quite low early in culture and increased markedly in all astrocytes with the duration in vitro. The concentration of d-serine in the culture medium increased in parallel with SR expression in the astrocytes. Microglia, identified by robust expression of Iba1, did not express SR. While the levels of glial fibrillary acidic protein (GFAP), glycine decarboxylase (GLDC) and phosphoglycerate dehydrogenase (PHGDH), the initial enzyme in the pathway converting glycine to l-serine, remained constant in culture, the expression of lipocalin-2, a marker for pan-reactive astrocytes, increased several-fold. The cultured astrocytes also expressed Complement-3a, a marker for a subpopulation of reactive astrocytes (A1). Astrocytes grown from mice with a copy number variant associated with psychosis, which have four copies of the GLDC gene, showed a more rapid production of d-serine and a reduction in glycine in the culture medium. These results substantiate the conclusion that A1 reactive astrocytes express SR and release d-serine under pathologic conditions, which may contribute to their neurotoxic effects by activating extra-synaptic NMDARs.