Scientists have been trying to understand the physiologic and genetic basis of schizophrenia for many years. Now researchers at the University of Basel's Biozentrum have assessed a group of 132 genes linked to the debilitating mental disorder. After following up on those findings with a zebrafish model, they confirmed that mutations in 30 of those genes cause pathological changes in the brain, and they learned more about the abnormalities that develop. The work has been reported in Cell.
"Of the 132 suspects, we were ultimately able to establish a more precise perpetrator profile for 30 genes," explained the leader of the research, Professor Alex Schier, Director of the Biozentrum, University of Basel, and a group leader at Harvard University in Cambridge. "One of the perpetrators is the transcription factor znf536, which controls the development of the forebrain. This brain region influences our social behavior and the processing of stress."
Transcription factors can change how other genes are expressed. The scientists used single-cell sequencing to reveal a role for znf536 in the development of neurons that are related to stress and social behavior. With their data on znf536 and the other genes they identified, they created an atlas. The researchers studied zebrafish mutants to catalog the problems that can arise in the brain when these genes contain errors.
While the exact causes of schizophrenia remain unclear, previous work has indicated that genes play a role in the disorder. Twin studies have suggested that the disease may also have an epigenetic component. Several areas of the genome and a variety of genes have been connected to the disease.
Symptoms of schizophrenia include difficulty with focusing and trouble sustaining activities as well as hallucinations, delusions and hearing voices, which can lead to a disturbed perception of reality. It affects an estimated 21 million people worldwide according to the World Health Organization, and people with the disorder are more likely to die early.
The disease is treatable with medications, but doctors and patients may have to work to find the proper dose, and those drugs don't cure the disorder. Specialty care can take a comprehensive approach that might even involve the patient’s family. There is plenty of room to improve these approaches through a better understanding of the disease etiology.
"The question of how the individual genes trigger schizophrenia remains open," said Schier. "It would be possible to investigate whether the genes we identified change similar brain regions in patients as in zebrafish." That research might open up new therapeutic avenues.
While it may seem like an unlikely research model, zebrafish are commonly used in molecular biology and behavioral studies. Learn more about zebrafish in the lab from the videos. A basic outline of how they are used is featured above, and a more in-depth discussion of how neuronal activity is measured in live zebrafish brains is featured below.