Genes, Physiology, Behavior All Linked in One Study

Using genetic engineering and brain probes, researchers have taken another step toward understanding the causes and mechanisms of schizophrenia.

Torfi Sigurdsson, Ph.D., a postdoctoral research scientist, and colleagues in the Department of Psychiatry at Columbia University College of Physicians and Surgeons, have found direct links among three key pieces in the complicated puzzle of what causes schizophrenia. Their findings were reported in the April 1 Nature.

The first piece is a genetic mutation: the 22q11.2 microdeletion, in which a stretch of DNA on chromosome 22 containing 30 to 40 genes is deleted. The consequence of this mutation is variable. Several studies have confirmed that people who carry this mutation have a 30-fold increased risk of developing schizophrenia.

In this study, the researchers genetically engineered a breed of mice carrying a mutation analogous to the human 22q11.2 microdeletion. In other words, the “same” genes were deleted in these mice.

Although it is not possible to test whether a mouse is psychotic, it is possible to measure the mouse's impairment in working memory; this is analogous to a cognitive deficit observed in human patients with schizophrenia. In this study, mice were trained in a spatial task, which required them to retrieve recently learned information. First, a mouse was directed to turn in one of two possible directions in a T-shaped maze. Next, the animals had to remember which direction they took before and turn in the opposite direction to find food. Thus, how quickly a mouse learned to perform the task is a measurement of its working memory.

Compared with mice without genetic mutation (the wild-type mice), the genetically engineered mice with the microdeletion were significantly slower to learn the task, suggesting that their working memory was impaired.

The third piece of the puzzle was how well the neural activities in the hippocampus and prefrontal lobe were synchronized when a mouse was performing the working-memory task. The electrical firings of the neurons in both regions were directly measured using tiny electrodes surgically implanted in the mouse brain.

As expected, the mutant mice had significantly lower synchrony between neurons in the hippocampus and those in the prefrontal lobe compared with the wild-type mice.

“Not only was the prefrontal-hippocampus connectivity during the task associated with how well [the mice] performed it, but even before they learned the task, the mutant mice showed reduced baseline connectivity,” said Joshua Gordon, M.D., Ph.D., an assistant professor at Columbia University and a psychiatrist at the New York State Psychiatric Institute, in an interview with Psychiatric News. Gordon is one of the authors of this study.

Previous brain imaging and electroencephalogram studies have shown a disconnection in the activities between the temporal and frontal lobes in people with schizophrenia. However, those are relatively crude measurements, as these instruments are able to show only the collective neural activities on a larger scale. “With the implanted microelectrodes, we can record the activities on the level of single neurons,” said Gordon.