Gene Linked to Compulsive Behaviors in Mice

By disabling a single gene in mice, scientists have created animals with symptoms that mimic those of people with obsessive-compulsive disorder (OCD). The researchers showed that the abnormal behaviors and brain functions could be reversed by either restoring a normal version of the gene in the mouse brain or by giving the animals a medication commonly used for human OCD.

OCD affects an estimated 2.2 million American adults. The disorder is marked by persistent intrusive thoughts (like an obsession with germs), repetitive actions (like compulsive hand-washing) and anxiety. It is typically treated with drugs known as selective serotonin reuptake inhibitors (SSRIs). These medications, however, are effective for only about half of patients with OCD.

In the new study, reported in the August 23, 2007, issue of Nature, the scientists used genetic engineering to create mice that lacked the SAPAP3 gene. SAPAP3 makes a protein that helps brain cells communicate via the glutamate chemical system. Most previous studies of OCD have focused on dysfunctions of other signaling molecules in the brain, like serotonin and dopamine. The researchers were thus surprised to discover OCD-like behaviors in the mice they'd created.

The mice seemed normal at first. But within a few months they began to engage in compulsive grooming, much like people with a form of OCD marked by compulsive hair pulling. Excessive grooming caused the mice to develop bald patches with open sores on their heads. They also exhibited anxiety-like behaviors. Further study showed that the mice had defects in a key brain circuit previously implicated in human OCD.

"The parallels with OCD were pretty striking," says Dr. Guoping Feng of Duke University. His research team was funded in part by NIH's National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Mental Health (NIMH) and National Institute of Environmental Health Sciences (NIEHS).

The scientists found that the animals responded to treatment with SSRIs, much like their human counterparts. The medication reduced both the excessive grooming and anxiety-like behaviors. The researchers also discovered that they could protect mice from developing OCD-like behaviors by injecting normal copies of the SAPAP3 gene into a brain region known as the striatum. The injections, they showed, corrected the malfunctioning circuitry in the striatum.

"Since this is the first study to directly link OCD-like behaviors to abnormalities in the glutamate system in a specific brain circuit, it may lead to new targets for drug development," Feng says. He and his colleagues are now working with clinical investigators to see if variants in the human SAPAP3 gene may be related to different forms of OCD, including compulsive hair-pulling (trichotillomania).