HAIFA, Israel (Press Release) — Identical twins only one of whom has schizophrenia differ in the expression of synaptic genes and in synaptic activity from the fetal development stage. This finding emerges from a new study undertaken at the University of Haifa and published in the prestigious journal Molecular Psychiatry from the Nature group.
For the first time, the study examined the genetic differences between pairs of identical twins, who would be expected to share an identical DNA sequence, when one of the twins suffers from schizophrenia while the other does not.
“Currently, most drugs for treating schizophrenia aim to calm the episodes and modulate dopamine activity. 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 concerning the future development of drugs and treatments for the disease focusing on these genes,” explained Prof. Shani Stern of the Sagol Department of Neurobiology at the University of Haifa, the author of the study.
Schizophrenia is a chronic mental disorder with a strong hereditary component that impairs daily functioning and features symptoms of psychosis. The causes for the development of the disorder are still unknown; theory and research in the field focus mainly on the abnormal activity of dopamine in the brain. In a previous study, Stern found a connection to change involving the synapses, the connecting points or intersections through which information passes between neurons in the brain.
The current study, conducted by Stern in cooperation with a team of researchers from the Salk Institute for Biological Studies in San Diego and Mt. Sinai School of Medicine in New York, sought to focus on the genetic differences in the synapses.
However, the researchers chose 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 of the twins suffers from schizophrenia while the other does not. The very low prevalence of schizophrenia in the population – between 1 and 1.5 percent – made it extremely difficult to locate such 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, Stern and colleagues used the Sendai reprogramming technology, as she regularly does in her laboratory. This method allows cells to be taken from any person and be “restored” to the status of stem cells. 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 monitoring of the cells immediately from their reclassification, effectively providing the genetic picture for the earliest fetal stages of human life.
Accordingly, in the current study, skin cells were collected from all the participants and reclassified as nerve cells of the hippocampus, allowing to monitor the hippocampus development almost from the moment of birth. In the first stage, the researchers found significant differences in the quantity of synapses created, as well as in their size and the quantity of connections between the neurons and the brain. Accordingly, three groups emerged: Twins suffering from schizophrenia had the lowest number of synapses, these had smaller currents than for the other subjects, and these twins had fewer connections between the neurons. All the twins in the control group – where neither twin has schizophrenia – had the largest quantity of synapses, the current flowing through them were larger, and the number of connections was also the highest. In the middle were the healthy siblings of the twins who suffer from schizophrenia, who constituted a distinct group: their synapses were more numerous with larger currents than those of their schizophrenic siblings, but less so than the healthy pairs of twins.
In the second stage, the researchers examined the differences between the twins on the level of RNA and DNA. They identified 20 significant genes whose expression differed between the schizophrenic twin and their healthy sibling. All the paths found involved synaptic mechanisms, where the affected twins were defective by comparison to the twins from the control group. “Since we can monitor genetic activity from the very earliest stages of the development of the cell, we found that the changes between the twin at the DNA and RNA levels begin during the fetal stage, just after the point when the fetus divides into two – a few days after the commencement of pregnancy,” explained Stern.
In the third stage, the researchers examined the electric potentials in the neurons and discovered the same picture of three distinct groups. The twins with schizophrenia showed the slowest development and a significantly lower level of synaptic activity and excitability by comparison to the twins in the control group. The electric and synaptic activity of the healthy subject with a schizophrenic sibling lay in between those of the schizophrenic twin and the healthy pairs of twins.
“Our study reinforces our previous finding concerning the connection between the defective development of the synapses in the brain and the development of schizophrenia. In the current study, we took an important step forward, identifying the genes whose expression changes and the stage at which this occurs. These findings open up new possibilities as we attempt to understand the causes behind the development of schizophrenia and, of course – the way to treat the disease,” concluded Stern.
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Preceding provided by Haifa University