Summary: Researchers identified rare genetic variation in two schizophrenia patients that increase schizophrenia-related behavior in mice. This mutation reduced the activation of NMDA receptors with high levels of glycine decarboxylase (GLDC), the enzyme that degrades glycine.
Mice with extra copies of the GLDC gene showed schizophrenia-like behavior, confirming their role in the condition. Advanced brain analysis showed that available glycines were significantly lower in certain brain regions and disrupt neural signaling.
Important facts:
Genetic link: Extra copy of the GLDC gene led to schizophrenia-like behavior in mice. Brain Disruption: Mutations reduced the availability of glycine in major brain regions and reduced loss of NMDA receptor function. was observed.
Source: University of Illinois
Genetic mutations found in two human patients with schizophrenia increased schizophrenia-related behavior in mice carrying the same mutation. This is a rare finding of direct genetic associations to psychosis, reports researchers from Urbana-Champaign University at the University of Illinois and colleagues from Massachusetts and Germany. .
This mutation increases the levels of GLDC, the enzyme involved in the regulation of glycine decarboxylase, the brain glycine. Glycine activates the receptor for the neurotransmitter glutamate, called the NDMA receptor.
“The genetics of schizophrenia are extremely complicated and it is rare that the mutations seen in patients directly link to the disease,” says Weh Rudolph, a professor of comparative biological sciences in Illinois. .
“Schizophrenia has not been diagnosed by any type of lab test or imaging. It is a clinical diagnosis based on symptoms. Hopefully, rare mutations of these types are important biochemistry to study us. It means that it can lead to tropologies and physiological pathways.”
The study began when genetic mutations were discovered in two patients with schizophrenia at McLean Hospital in Belmont, Massachusetts. They had multiple copies of the section of DNA containing the genes of GLDC. Interested whether the mutations contributed to their symptoms, the MacLean team studying the patients contacted Rudolf’s lab to create a line of mice with the same mutation.
Mice carrying mutations similar to those in human patients also exhibited schizophrenia-related behavior.
To further narrow down the genetic link, the researchers then developed a mouse strain containing multiple copies of only a few genes contained in a larger chromosomal segment that is repeated in the patient, followed by a single gene: GLDC has been developed.
Rudolph, who is partnered with the Illinois Neuroscience Program and Carl R. Vose’s Institute of Genomic Biology, said:
To understand why multiple copies of the GLDC gene are solely responsible for behavioral symptoms, researchers have investigated in detail what is happening in the mouse brain, particularly glycine levels and the function of the NDMA receptor. Ta.
“We hypothesized that additional copies of GLDCs had low levels of glycine in the brain because they degrade glycine. There is no sufficient glycine to help activate the NDMA receptors,” an Illinois postdoctoral study. Maltesh Kambali, the author, said he was the first author of the paper.
“We measured an increase in the activity of GLDC enzymes in the mouse brain.
However, when researchers measured glycine levels in mice’s brains, there did not appear to be much difference between excess GLDC and those with healthy mice. So Rudolf’s team turned to his German colleagues who developed sophisticated methods of tracking glycine in their brains.
The German team found that although the overall amount of glycine throughout the brain is similar, the amount of glycine outside the neurons is available to help activate the NDMA receptors I did. GLDC’s.
To see why this area of the brain was so affected, Rudolf’s team worked with researchers at Harvard Medical School to help the brain function in the affected subregion of the brain called the dentate gyrus. A study was conducted.
They identified a decrease in the activity of neural synapses, the active junction that sends signals between neurons. They identified differences in long-term potentiation, which is a sustained reinforcement of activity at the synapse during the learning process.
“We saw how glycine measurements and long-term enhancement measurements show convergent changes in this dentate gyrus region, but they did not change in other regions of the hippocampus. That’s interesting because , because one theory links development of psychosis to the activity of the dentites, and therefore our findings fit that theory,” said Kanbari.
The Illinois team then performed biochemical analysis of the dentate gyrus of mice using additional copies of GLDC. They say that several pathways previously associated with schizophrenia reduce activity, and that an increase in GLDC and a associated reduction in glycine are indeed sufficient to inhibit the function of the NMDA receptor, shows that it is involved in the observed symptoms of schizophrenia.
The researchers published their findings in the Journal of Molecular Psychiatry.
“This study demonstrated at multiple levels how GLDC functions as a novel regulator of NMDA receptors,” Rudolf said.
“NMDA receptor dysfunction has been shown to be important in the pathophysiology of schizophrenia. However, since NMDA receptors are essential for many brain functions, including learning and memory, this finding is not limited to this. It is not related to illness.”
The work includes the National Institutes of Health, the Shelbert Frasier Research Institute at McLean Hospital, the Stanley Psychiatric Research Center at the Broad Institute at Harvard and Mitt, and the Harvard Brain Science Initiative Bipolar Disorder Seed Assistance. Supported by money.
Funding:
This work was conducted by the National Institutes of Health grants R21MH104505, R56MH112642, R01MH115957, R01HD096326, R01MH123155, R01NS093200, P50MH115874, R01MH123993, R01MH12393, R01MH051290, P50MH094271 and U01AA020889.
About this schizophrenia and genetics research news
Author: Liz Ahlberg Touchstone
Source: University of Illinois
Contact: Liz Ahlberg Touchstone – University of Illinois
Image: Image credited to Neuroscience News
Original Research: Closed Access.
“Increasing the copy number of glycine decarboxylase (GLDC) associated with psychosis reduces extracellular glycine and impairs NMDA receptor function,” Uwe Rudolph et al. Molecular Psychiatry
Abstract
Increased copy number of glycine decarboxylase (GLDC) associated with psychosis reduces extracellular glycine and impairs NMDA receptor function
Glycine is a mandatory coagonist of excitatory NMDA receptors in the brain, especially the obnoxotropic moment, and is hypothesized to be essential for the development of psychotic associations and memory of psychotic content.
Drugs that regulate glycine levels have been developed clinically to improve cognition in schizophrenia. However, the functional association of the regulation of glycine metabolism by endogenous enzymes is unknown.
Trialization of genes encoding the glycine metabolism enzyme glycine decarboxylase (GLDC) using the Chromosomal Institute of Technology Allele Series in mice is as seen in small, hyper-lactory marker chromosomes in psychotic patients – psychopathic layer Report as measurements to be measured as measured as measured as measured as. Dentically photofluorescence resonance energy transfer (FRET) suppresses long-term potentiation (LTP) of MPP-DG synapses, and suppresses the CA3-CA1 synapses, leading to the activity of biochemical pathways involved in schizophrenia and mitochondrial bioenergies. It lowers and shows defects in behaviour like a plant-like body. Parts of the dentite that are known to be dependent on activity, such as prepulse inhibition, surprising habituation, potential suppression, working memory, sociability, and social preferences.
Our results show that GLDC negatively regulates long-term synaptic plasticity in the dentate gyrus in mice, suggesting that an increase in GLDC copy number may contribute to the development of psychosis in humans It’s there.
