No single gene mutation causes schizophrenia, but a growing number of genetic variations are now known to increase a person's risk of developing the disorder. New work in mice suggests that one such variation, which alters a gene called Rapgef6, may disrupt neural circuits involved in fear learning and anxiety.

Rapgef6 belongs to a family of genes whose members have been linked to several mental illnesses, including depression, anxiety disorders, and schizophrenia. Although studies have found Rapgef6 to be disrupted in people with schizophrenia, it was not known how such deficiencies affect the brain. A research team led by two-time (2003, 2006) NARSAD Young Investigator grantee Joseph A. Gogos, M.D., Ph.D., at Columbia University studied mice lacking the gene to determine how loss of Rapgef6 impacts brain function and behavior. Their results were published June 9th in the journal Translational Psychiatry.

In the team’s experiments, mice without Rapgef6 exhibited significant deficits in fear learning. When presented with a sound that had previously been paired with an unpleasant foot shock, mice lacking Rapgef6 tended to continue exploring their environment. On the other hand, animals in which Rapgef6 was intact showed fear: when they heard the sound, they froze in place. Similarly, when the researchers delivered a shock in an environment scented with a particular odor, mice without Rapgef6 failed to develop fear of similar surroundings. Mice without Rapgef6 were also mildly hyperactive and showed less signs of anxiety than other mice.

The researchers found that cells in the amygdala and hippocampus––two parts of the brain critical for fear processing––normally express Rapgef6. Fear conditioning activates neurons in these regions, but the researchers learned that in mice without Rapgef6, amygdala and hippocampus neurons were unresponsive to conditions that trigger fear learning in normal mice. When they examined the structure of cells in the hippocampus and amygdala, the scientists saw that in mice without Rapgef6, certain neurons had fewer of the small surface projections that receive signals from neighboring cells.

Hyperactivity and changes in fear-related behavior are both linked with schizophrenia. There is also evidence that amygdala dysfunction may underlie the “negative symptoms” of the disorder, such as a lack of pleasure in everyday life and a flat affect. Further studies of mice without Rapgef6 could help scientists better understand these effects, the researchers say.

Three other former NARSAD grantees were involved in the research: Mirna Kvajo, Ph.D. (2009 Young Investigator); Maria Karayiorgou, M.D. (1998 Young Investigator; 2010 Distinguished Investigator); and Vadim Bolshakov, Ph.D. (2004, 2006 Independent Investigator, 2013 Distinguished Investigator).

Read the research paper.