Summary: In two patients with schizophrenia, scientists discovered a rare genetic mutation that made rabbits more likely to exhibit schizophrenia-related actions. The mutation led to higher levels of glycine decarboxylase ( GLDC ), an enzyme that degrades glycine, reducing NMDA receptor activation.
Mice with more duplicates of the GLDC protein exhibited schizophrenia-like behaviors, confirming its position in the state. Advancement in mental analysis demonstrated that the available glycine was significantly lower in a particular brain region, causing a disruption to neuronal signaling.
Important Information:
- Biological Link: Extra duplicates of the GLDC protein led to schizophrenia-like actions in animals.
- Mental Disruption: The mutation lowered glutamine presence in a crucial mental area, impairing NMDA receptor work.
- Neurological Effect: Reduced neural activity and impaired learning-related mental features were observed.
Origin: University of Illinois
Researchers at the University of Illinois Urbana-Champaign and acquaintances in Massachusetts and Germany report that a genetic mutation discovered in two people patients with schizophrenia even increased schizophrenia-related behaviors in mice with the same gene, a rare discovering of a strong genetic connection to illness.
The gene increases levels of glutamine decarboxylase, or GLDC, an protein responsible for regulating glutamate in the mind. Glycine produces receptors for the hormone serotonin, called NDMA receptors.
” The biology of dementia is very difficult, and it is rare that variants found in patients may be linked directly to the disease”, said review leader , Uwe Rudolph, a doctor of , analytical biosciences , at Illinois.
” Schizophrenia is still a scientific diagnosis based on symptoms, not a lab test or scanning, but it is still not yet diagnosed by any kind of lab test or mri.” The wish is that these kinds of uncommon mutations can help us discover the crucial chemical and biological pathways to study.
Two people at McLean Hospital in Belmont, Massachusetts, both diagnosed with schizophrenia, discovered a genetic mutation. A part of DNA that contained the dna for GLDC contained several copies. The McLean staff, who were studying the patients, reached out to Rudolph’s facility to develop a collection of mice carrying the same mutation, curiously wondering whether the mutation might have caused their symptoms.
The animals with mutations identical to those in the human patients likewise showed schizophrenia-associated actions.
The researchers then created traces of mice with many copies of just a few of the several genes contained within the larger gene section repeated in the patients, and finally a single protein: GLDC, to further narrow down the hereditary link.
” We found that extra copies of the GLDC gene alone were sufficient to render the schizophrenia-like behaviors we had observed”, said Rudolph, who also is affiliated with the , Neuroscience Program , and the , Carl R. Woese Institute for Genomic Biology , at Illinois.
The researchers examined what was happening in the mice’s brains, specifically the levels of glycine and the function of NDMA receptors, to understand why multiple copies of the GLDC gene would be solely to blame for the behavioral symptoms.
We made the hypothesis that extra GLDC copies would cause the brain to have a lower glycine level because it degrades glycine. The first author of the paper, Illinois postdoctoral researcher Maltesh Kambali, said,” There wouldn’t be enough glycine to help activate the NDMA receptors.”
” We observed an increase in the activity of the GLDC enzyme in the brains of our mice, which would indicate that as well.”
However, when the researchers measured glycine levels in their mice’s brains, it appeared that there wasn’t a noticeable difference between those with extra GLDC and healthy mice. Rudolph’s team then turned to German colleagues who had developed sophisticated methods for monitoring glycine in the brain.
The German team discovered that while the overall glycine content was comparable, the glycine content outside of the nerve cells and capable of activating NDMA receptors was significantly lower in a hippocampus subregion in mice with multiple GLDC copies.
Rudolph’s team collaborated with Harvard Medical School researchers to create functional studies on the dentate gyrus, which is the brain’s affected region, to understand why this area of the brain was so affected.
They found that the neural synapses, which are the active junctions where neurons communicate, are less active. They identified differences in long-term potentiation, a steady increase in activity in the synapse throughout the learning process.
We observed that the dentate gyrus region’s glycine measurements and long-term potentiation measurements, but not other hippocampus regions, were exhibiting converging changes. One theory attributes the activity of the dentate gyrus to the development of psychosis. So our findings fit with that theory”, Kambali said.
The Illinois team then examined the dentate gyrus in the GLDC-extended mice for additional GLDC plasmids. They discovered that some previously thought-provoking pathways had decreased activity, suggesting that the GLDC and resulting GLDC decrease was indeed sufficient to impede the function of NMDA receptors and was responsible for the schizophrenia symptoms they had observed.
The researchers published their , findings , in the journal , Molecular Psychiatry.
Rudolph said,” This study demonstrated at multiple levels how GLDC serves as a novel NMDA receptor regulator.”
” The function of NMDA receptors has been demonstrated to be crucial in the pathophysiology of schizophrenia. However, this finding also applies to other diseases, since the NMDA receptor is required for many brain functions, including memory and learning.
The National Institutes of Health, the Shervert Frazier Research Institute at McLean Hospital, the Stanley Center for Psychiatric Research at Harvard and MIT, and a seed grant for the Harvard Brain Science Initiative Bipolar Disorder, were all funding this study.
Funding:
This work was supported by the National Institutes of Health grants R21MH104505, R56MH112642, R01MH115957, R01HD096326, R01MH123155, R01NS093200, P50MH115874, R01MH123993, R01MH108665, R01MH051290, P50MH094271 and U01AA020889.
About this news from genetics and schizophrenia research
Author: Liz Ahlberg Touchstone
Source: University of Illinois
Contact: Liz Ahlberg Touchstone – University of Illinois
Image: The image is credited to Neuroscience News
Original Research: Closed access.
Uwe Rudolph and colleagues ‘ study found that an increase in the copy number of the glycine decarboxylase ( GLDC ) associated with psychosis impairs the function of the NMDA receptor. Molecular Psychiatry
Abstract
Extracellular glycine is reduced and impaired by an increase in the copy number of the glycine decarboxylase ( GLDC ) associated with psychosis.
Glycine is a required co-agonist at dentate gyrus, which is thought to be crucial for the development of psychotic memories and associations with psychotic content, in the brain.
For improving cognition in schizophrenia, drugs are in clinical development that can modulate glycine levels. However, it is unclear whether endogenous enzymes ‘ control of glycine metabolism has a functional impact.
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.
