When only one of two identical twins suffers from schizophrenia (the incurable mental disorder of recurrent episodes of psychosis, a general misperception of reality, paranoia, hallucinations, social withdrawal and disorganized thinking) they differ in the expression of synaptic genes and the synaptic activity of the stage of fetal development.
Schizophrenia affects 1% to 1.5% of the world’s population, and genetics, epigenetics, and environmental factors are known to play a role in this disorder. The synapse is the gap between one neuron and another. Synaptic activity is the firing of an electrical charge by one nerve cell onto another neuron, making the postsynaptic neuron more or less likely to fire its action potential (a rapid sequence of changes in voltage across a membrane).
This finding emerges from a new study carried out at the University of Haifa and published in the Nature prestigious magazine of the group Molecular Psychology. It was led by Professor Shani Stern from Sagol’s neurobiology department and titled “Monozygotic twins discordant for schizophrenia differ in synaptic maturation and transmission.”
The researchers examined genetic differences between pairs of identical twins who would be expected to share an identical DNA sequence when one twin has schizophrenia while the other does not.
“Currently, most drugs to treat schizophrenia aim to calm episodes and modulate the activity of a brain neurotransmitter called dopamine,” Stern said. “We believe that the results of this study, which for the first time identified specific genes in which changes occur, are grounds for cautious optimism regarding the future development of drugs and disease treatments targeting these genes “, explains the author of the study. to study.
Genetics of schizophrenia
The causes of the development of schizophrenia are still unknown; theory and research in the field focuses primarily on abnormal dopamine activity. In a previous study, Stern found a connection to the change involving synapses, the connection points or intersections where information passes between neurons in the brain.
In the current study that Stern led in cooperation with a team of researchers from the Salk Institute for Biological Studies in California and the Mt. Sinai School of Medicine in New York, the team aimed to focus on genetic differences in synapses.
However, they decided to examine genetic differences between individuals who would not be expected to show such differences: pairs of identical twins who should share the same DNA sequence, where one twin suffers from schizophrenia while the other does not.
The very low prevalence of schizophrenia in the population made it extremely difficult to locate these identical twins, but eventually two pairs of twins were found, as well as three pairs of identical twins without schizophrenia, who served as a control group.
In the study, the team used what’s called Sendai virus reprogramming technology, as they routinely do in their lab. This method allows cells to be taken from anyone and “restored” to stem cell status. They can then be reclassified as any type of cell, and the new cells will retain exactly the individual’s DNA sequence. This method also allows the tracking of cells immediately after their reclassification, effectively providing genetic imaging of the early fetal stages of human life.
In the current study, skin cells were collected from all participants and reclassified as hippocampal nerve cells in the brain, allowing hippocampal development to be monitored almost from the time of birth In the first stage, the researchers found significant differences in the amount of synapses created and their size, and the number of connections between neurons and the brain.
Three groups emerged: the twins with schizophrenia had fewer synapses and smaller currents than the other subjects, as well as fewer connections between neurons. All the twins in the control group in which neither twin was schizophrenic had the most synapses, the current flowing through them was the greatest, and the number of connections was also the highest.
In the middle were the healthy siblings of the schizophrenic twins and they were a different group: their synapses were more numerous with larger currents than those of their schizophrenic siblings but fewer than the healthy twin pairs.
In the second stage, the researchers examined the differences between the twins at the level of RNA and DNA. They identified 20 significant genes whose expression differed between the schizophrenic twin and their healthy sibling. All of the pathways found involved synaptic mechanisms in which affected twins were defective compared to control twins.
“Because we can monitor genetic activity from the earliest stages of cell development, we found that changes between the twin at the DNA and RNA levels begin during the fetal stage, just after the point when the fetus splits into two … a few days after the pregnancy begins,” Stern explained.
In the third stage, the researchers examined the electrical potentials of the neurons and discovered the same image of three different groups. Twins with schizophrenia showed slower development and a significantly lower level of synaptic activity and excitability compared to twins in the control group. The electrical and synaptic activity of the healthy subject with a schizophrenic sibling was between that of the schizophrenic twin and the healthy twin pairs.
“Our study reinforces our previous finding about the connection between the defective development of synapses in the brain and the development of schizophrenia. Here, we took an important step forward, identifying the genes whose expression changes and the stage in which it occurs. These findings open up new possibilities as we try to understand the causes behind the development of schizophrenia and, of course, how to treat the disease,” Stern concluded.
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