When only one of two identical twins suffers from schizophrenia – the incurable mental disorder of reoccurring episodes of psychosis, a general misperception of reality, paranoia, hallucinations, social withdrawal, and disorganized thinking – differ in the expression of synaptic genes and synaptic activity from the fetal development stage.
Schizophrenia affects about 1% to 1.5% of the world 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 – to another neuron, making the postsynaptic neuron either more or less likely to fire its action potential (a speedy sequence of changes in the voltage across a membrane.)
This finding emerges from a new study carried out at the University of Haifa and published in the Nature group’s prestigious journal Molecular Psychology. It was led by Prof. Shani Stern of the Sagol neurobiology department and entitled “Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission.”
The researchers examined the genetic differences between pairs of identical twins who would have been 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 the activity of the 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 concerning the future development of drugs and treatments for the disease focusing on these genes,” explained the author of the study.
Schizophrenia genetics
The causes for the development of schizophrenia are still unknown; theory and research in the field focus mainly on dopamine’s abnormal activity. 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.
In the current study that Stern led in cooperation with a team of researchers from California’s Salk Institute for Biological Studies and Mt. Sinai School of Medicine in New York, the team aimed to focus on the genetic differences in the 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 of the twins suffers from schizophrenia while the other does not.
The very low prevalence of schizophrenia in the population 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, the team used what is called the Sendai-virus reprogramming technology, as she regularly does in her lab. 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.
In the current study, skin cells were collected from all the participants and reclassified as nerve cells of the hippocampus in the brain, making it possible to monitor hippocampus development almost from the moment of birth. In the first stage, the researchers found significant differences in the quantity of synapses created and in their size, and the number of connections between the neurons and the brain.
Three groups emerged – twins suffering from schizophrenia had the lowest number of synapses and smaller currents than the other subjects, as well as fewer connections between the neurons. All the twins in the control group in which neither twin was schizophrenic had the largest quantity of synapses, the current flowing through them was larger, and the number of connections was also the highest.
In the middle were the healthy siblings of the twins who suffered from schizophrenia and 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 in which 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 beginning of the pregnancy,” Stern explained.
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 in 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. Here, 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.