Disruption in Brain Connection Linked to Genetic Defect in Schizophrenia

In what may provide the most compelling evidence to date, researchers at Columbia University Medical Center have illuminated how a genetic variant may lead to schizophrenia by causing a disruption in communication between the hippocampus and prefrontal cortex regions of the brain, areas believed to be responsible for carrying out working memory. Findings are published in the current online edition of Nature.

This discovery coincides with the 15th anniversary of the first identification of the link between schizophrenia and a genetic mutation – a microdeletion on human chromosome 22 – known as 22q11 deletion, by Columbia Psychiatry researcher Maria Karayiorgou, M.D., a coauthor on the research. Previous studies have shown that approximately 30 percent of patients with this deletion will go on to develop schizophrenia.

“We know that this genetic deficit predisposes us to schizophrenia, and now we have identified a clear pathophysiological mechanism of how this deletion confers this risk for schizophrenia,” said Dr. Karayiorgou.

Dr. Karayiorgou discovered the link between the 22q11 mutation and schizophrenia in 1995. Since then, Dr. Karayiorgou and Joseph A. Gogos, M.D., Ph.D, a senior author on the research, have established and pursued research focusing on the neurobiology of this mutation.

Though schizophrenia is best known for its delusions and hallucinations, it is the disease’s impact on such cognitive abilities like working memory – a key element of executive functioning – that best predict how well a person will function in society.

Using a mouse model with the 22q11 deletion, senior authors Joshua Gordon, M.D., Ph.D., and Joseph A. Gogos, M.D., Ph.D., and their teams, recorded the neural activity of the mice while they performed a cognitive task of working memory, and found that their performance was either completely disrupted, or was impaired, compared to that of the healthy mice.

(Dr. Karayiorgou is professor of psychiatry, Dr. Gogos is associate professor of physiology and neuroscience, and Dr. Gordon is assistant professor of psychiatry at Columbia University Medical Center).

In healthy mice, the hippocampus sends spatial information to the prefrontal cortex, but in the mouse model of the 22q11 mutation there is a breakdown in the connection and this communication is either weakened or fails completely.

As part of the cognitive trial, the mice were tested as they navigated a t-shaped maze. In order to successfully complete the task, the mice had to recall the direction in which they traveled, and then choose to go in the opposite direction to receive their next reward. While the healthy mice easily learned the task, mice carrying the schizophrenia mutation took longer to master it, demonstrating a behavioral deficit of the task in the mouse model of schizophrenia.

“We found that successful completion of the task in our healthy mice required the two regions of the brain – the hippocampus and the prefrontal cortex – to work together, and in our mouse model, the information transfer was less efficient, or was unable to take place at all,” said Dr. Gordon.