Identical twins, one has schizophrenia and the other is healthy. The difference in gene expression is already in the embryonic stage

This was found in a new study conducted at the University of Haifa and published in the prestigious journal Molecular Psychiatry from NATURE

Identical twins, only one of whom has schizophrenia, differ in synaptic gene expression and synaptic activity already in the developmental stages of the fetus, according to a new study conducted at the University of Haifa and published in the prestigious journal  Molecular Psychiatry from NATURE and examined for the first time the genetic difference between pairs of identical twins, who are supposed to have the same genetic load - when one suffers from schizophrenia and the other does not.

"Today, most of the medications for schizophrenia deal with the calming of episodes and the modulation of dopamine activity. We believe that the results of the study, which found for the first time specific genes in which changes occur, inspire cautious optimism regarding the development of future medications and treatments for the disease - which will focus on these genes," said Prof. Shani Stern of Purple Circle for neurobiology at the university, the research editor.

Schizophrenia is a chronic mental disorder, with a high heritability factor, that impairs daily functioning and is characterized by symptoms of psychosis. To this day, the causes of the development of the disorder are unknown and most of the theory and research revolves around abnormal activity of dopamine in the brain. In a previous study by Prof. Stern, she found a connection to changes related to synapses - the connection points or junctions where information passes between the neurons in the brain. Therefore, in the current study, the researchers, Prof. Stern from the Sagol Department of Neurobiology in collaboration with a team of researchers from the Salk Institute and the Mount Sinai School of Medicine, asked to focus on genetic differences in synapses.

However, in the current study, they chose to examine genetic differences between those who should not have such differences - pairs of identical twins, who are supposed to carry the same genetic load - when one of the twins suffers from schizophrenia and the other does not. In light of the difficulty in finding such twin pairs, two pairs of twins participated in the study, one suffering from schizophrenia and the other not, and three more pairs of identical twins without schizophrenia, who served as the control group.

In the research Prof. Stern used the technology used in her laboratory of "stem cell reprogramming" (Sendai Reprogramming). With this method it is possible to take cells from any person and "return them back" to the state of stem cells, and from there sort them back into any type of cell we want, when the new cell carries exactly the same genetic load of the person. Thanks to this method, it is also possible to follow the cell immediately from the moment of its re-sorting, and thus actually get the genetic picture that corresponds to the period when that person would have passed through in his first moments.

Thus in the current study, cells were taken from all participants and re-sorted into neurons of the hippocampus, almost from the moment of their birth. In the first stage, the researchers found significant differences in the amount of synapses formed, their size and the amount of possible connections between the neurons in the brain: the twins who suffered from schizophrenia had the fewest amount of synapses, they were smaller compared to the others and the number of connections between the neurons was the smallest; All the twins from the control group, meaning the one where neither twin suffers from schizophrenia, had the largest amount of synapses, they were the largest and the number of connections was the largest. In the middle were the healthy siblings of the twins who suffered from schizophrenia, who actually formed a group of their own: they had more synapses and were larger compared to their siblings with schizophrenia, but less than the healthy pairs.  

In the second step, the researchers examined the differences between the twins at the RNA and DNA level and identified 20 significant genes whose expression differed between a schizophrenic twin and his healthy brother. All the pathways found were related to synaptic mechanisms and their control was impaired compared to the twins from the control group. The findings revealed that the changes in the DNA level began at a stage that corresponds to the embryonic stage, and in fact, shortly after the time when the embryo split into two.

In the third step, the researchers tested the electrical voltage in the neurons and discovered a picture similar to the first finding: twins suffering from schizophrenia had a slow development and a significant decrease in the amount of synaptic activity, compared to the control group twins. The electrical and synaptic activity of the healthy twin to the brother with schizophrenia was found in the range between the sick twin and the healthy twin pairs.

"Our study once again reinforces our previous finding that talks about the connection between the poor development of synapses in the brain and the development of schizophrenia, when in the current study we took another significant step forward and identified the genes whose expression changes and the timing of these changes. These findings open a new door for trying to understand the The causes of the development of schizophrenia and of course - the way to treat it", Prof. Stern concluded.