Gene knockout may cheer up mice

Pharmacy scientists at the University of Maryland, Baltimore (UMB) have identified antidepressant and anti-anxiety behaviors in tests of mice lacking the gene.

Writing in the journal BMC Neuroscience, Elisabeth Barbier, PhD, postdoctoral fellow at the School of Pharmacy, and Jia Bei Wang, PhD, professor at the School, concluded after running a battery of standard behavioral tests on the mice without the PKCI/HINT1 gene that it may have an important role in mood regulation.

Mice in the study that had what is being called the "despair" gene eventually gave up trying to avoid apparent danger in tests involving swimming or exposure to light -- conditions disliked by mice. Mice without the gene kept trying to escape from danger, perhaps abnormally.

"The knockout mice [without the gene] displayed behaviors indicative of changes in mood function, such as increased perseverance and reduced anxiety in open spaces," Wang said.

The causes of mood dysfunction, as seen in depressive and bipolar disorders, are still not fully understood. They are believed to be multifactorial and involve heredity, changes in neurotransmitter levels, altered neuroendocrine function, and psychosocial factors.

"We don't yet know why the deletion of the gene altered the mood status of the mice," says Wang, a neuroscientist. She says the protein encoded by the gene could be a potential target for development of diagnostic or therapeutic agents that one day might be used for depression, bipolar disorders or schizophrenia. In addition, the knockout mice might be useful as models to study mania. Currently no mania animal model is available.

The researchers discovered the gene while studying the biological receptors in brain cells that respond to opioid drugs. "I thought [such a] receptor can't be making the entire change in the body. There must be other proteins," Wang says. The scientists learned that the gene had already been cloned at Columbia University in the City of New York, where medical researchers were studying its possible role in cancer.

Five years ago, Wang searched scientific literature and found no psychological function for the gene, although it is concentrated in the brain. But she was convinced of its importance because the protein for the gene appears in the genome of living things all along the evolutionary spectrum -- from bacteria and fungi to worms to humans. "It must be important. It must be essential otherwise why would all these creatures have it?" Wang says.

Also significant, she says, is that other studies have shown that cadavers of people with biopolar and schizophrenia disorders had less protein encoded by the gene in their brains.

By screening large libraries of chemicals, Wang will next search for compounds that may induce changes in the protein of the gene.

Meanwhile, she says, "We are showing the scientific community that this is an important protein that may have something to do with schizophrenia, bipolar [disorders], and depression. But we don't know how it works. Certainly this opens the door for work on discovering the mechanism, how it changes behavior. This is the first paper to show that this protein is important to these conditions."

The causes of mood dysfunction, as seen in depressive and bipolar disorders, are still not fully understood. They are believed to be multifactorial, involving heredity, changes in neurotransmitter levels, altered neuro-endocrine function, and psychosocial factors.

Speaking about these results, Wang said: "Although we don't yet know why the deletion of the gene altered the mood status of the mice, what we have learned about the importance of this gene in mood function and its involvement in human mental disorders is interesting. The protein encoded by this gene could be a potential drug target for development of diagnostic or therapeutic agents that one day might be used for depression, bipolar or schizophrenia disorders. In addition, the knockout mice might be useful as a model to study mania, as there is no other animal model available yet."

According to the February 2008 issue of the journal PLoS Medicine, more prescriptions in 2007 were dispensed for antidepressants -- 232.7 million nationwide -- than for drugs of any other type. U.S. sales of antidepressants totaled $11.9 billion, according to data from IMS Health, Inc.