More than 15 years after a genetic variant was shown to predispose its carriers to schizophrenia, scientists have finally uncovered how the chromosomal abnormality might cause symptoms of the brain disorder. By studying mice with a similar gene defect, the research team from Columbia University Medical Center linked abnormalities in behavior to a faulty connection between the hippocampus and the prefrontal cortex—two brain areas important for learning and memory.



"We know that this genetic deficit predisposes us to schizophrenia, and now we have identified a clear pathophysiological mechanism of how [it] confers this risk…," Maria Karayiorgou, co-author on the study published April 1 in Nature and lead author on the 1994 publication identifying the genetic variant in Brain Research, said in a prepared statement. (Scientific American is part of Nature Publishing Group.)



Thirty percent of people carrying the variant—a small deletion of genetic material on chromosome 22—will go on to develop the schizophrenia, making it "one of largest genetic risk factors" for the disease, according to senior author Joshua Gordon. The odds of someone in the general U.S. population developing the disorder are one in 100, but those odds jump to one in 10 for people with an affected first-degree relative, and one in three for people with a schizophrenic identical twin, highlighting the role of genes in the development of the disease.



People with schizophrenia suffer from a loss of contact with reality, confused thinking, delusions and hallucinations—usually hearing internal voices. Scientists think that no single gene defect causes the disease. Rather, they theorize that several genetic variations passed on haphazardly from one generation to the next are to blame, along with certain environmental factors—making it harder to understand how various neurological processes might be going wrong. But by spotting interrelated behavioral and physiological differences in their mouse model, the Columbia team has implicated communication between brain areas as one such process.



The researchers measured the neural activity between the hippocampus and the prefrontal cortex while normal mice and those with the genetic deletion performed a task—learning and remembering the whereabouts of a food reward on a T-shaped maze. "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," Gordon said in a prepared statement. "And in our mouse model, the information transfer was less efficient or was unable to take place at all." The experiment even revealed a dose effect—the mice who had the least communication between the hippocampus and the prefrontal cortex turned in the worst performances negotiating the maze.



The researchers are excited to have discovered a possible mechanism linking the genetic variant to the behavioral deficits in schizophrenia. "We now know that one of the consequences of that deletion is to disrupt functional communication between these two brain regions, and we have evidence from the study that the disruption actually has an impact on a cognitive behavior that is disrupted in patients," said Joseph Gogos, the study's other senior author, in a prepared statement. "It is possible that similar abnormalities in functional connectivity may also account for other symptoms of the disease and can be used to better assess treatment response, and, most importantly, to develop new medications."



In addition to its role in the heightened risk for schizophrenia, "the gene deletion also increases the risk for other cognitive and psychiatric disorders," said Dolores Malaspina, a psychiatrist at New York University Langone Medical Center who was not involved in the study. The study is "an important step in illuminating how the deletion may be related to a brain dysfunction that is present in some people with mental illness," she added. "This is important information whether or not any of [the genes involved] turn out to be common causes of schizophrenia in the population."