Mental disorders are found worldwide, and approximately one in four adults in the United States suffers from a diagnosable mental disorder in a given year. The biological causes of many mental disorders are unknown and, thus, the mode of treatment is not always obvious. Obsessive-Compulsive Disorder (OCD) is a mental disorder that affects about 2.2 million American adults, a third of whom develop symptoms as children. The illness is characterized by incessant and uncontrollable desires to perform certain actions that interfere with daily life. Recently, a group of scientists from Duke University identified a gene that, when removed from mice, causes OCD-like behavior. This new mouse model of the illness could help lead to a better understanding of OCD as well as to the development of new treatments.

What is Obsessive-Compulsive Disorder?

According to the National Institute of Mental Health, Obsessive-Compulsive Disorder is an anxiety disorder that is characterized by recurrent, unwanted thoughts (obsessions) and/or repetitive behaviors (compulsions). People with OCD are often so troubled by these persistent thoughts that they perform elaborate “rituals” in order to temporarily relieve their intense anxiety. For example, some OCD sufferers are pathologically obsessed with germs, so they wash their hands repeatedly or in an elaborate manner. If the obsession is with intruders, people with OCD may check the locks on their doors numerous times. Sometimes people with OCD may be afraid that something bad will happen to a loved one, so they become obsessed with doing certain things in order to avoid bad luck, even when they realize that the behavior is illogical. While many healthy people may also have these habits, a person is not considered to have OCD unless the actions interfere with his or her life or begin to cause distress or anxiety.

Currently there are several options for treating Obsessive-Compulsive Disorder. Like clinical depression, OCD is commonly treated with a class of drug called serotonin specific reuptake inhibitors, or SSRIs. There are many SSRIs on the market, including fluoxetine, better known by its brand name, Prozac. Although it is unclear if low levels of serotonin, a neurotransmitter used be nerve cells to communicate, are directly responsible for causing these illnesses, pharmacologically elevating serotonin levels with SSRIs frequently provides some symptomatic relief for patients. In addition, people with OCD may benefit from behavioral therapy. With the help of a therapist, patients are offered safe environments to confront the things that distress them. For example, if an OCD patient usually experiences the compulsion to wash his hands exactly six times before eating, a therapist can encourage him to wash just once and reinforce that he will be just fine despite not completing his ritual. Despite established therapies, better treatments are needed because current options are not always effective for all OCD sufferers.

How can You Tell if a Mouse is Anxious?

When Dr. Guoping Feng and his colleagues removed a gene called SAPAP3 from mice, they were intending to study the function of the protein encoded by the SAPAP3 gene. When they engineered the mice, however, they got a surprise. They noticed that their mice developed bald patches on their heads. This baldness was not associated with aging, mice as young as four months old had bald patches. The researchers suspected that the patches were due to the animal’s behavior, so they monitored the mice with unobtrusive cameras. The cameras revealed that the mice could not stop grooming themselves. They groomed themselves so excessively that they wore their fur away — they were obsessed with cleanliness! Because this behavior is reminiscent of the obsessive behavior of some OCD patients, the researchers went on to perform behavioral tests on the mice to determine if they exhibited other features of OCD. Sure enough, the mice exhibited anxiety-like behaviors, such as being slower to enter and quicker to exit risky environments. Although there is debate in the field about how best to measure anxiety in mice, and whether it is actually comparable to the anxiety felt by humans, the cumulative evidence from this study indicates that mice engineered to lack SAPAP3 mirror many of the features of OCD and can be considered as a model of the illness.

What We can Learn from Mice

Surprisingly, the diverse behaviors exhibited by these mice all resulted from the deletion of just one gene, SAPAP3. Humans also have the SAPAP3 gene, although it is unclear at this time if SAPAP3 is directly involved in the development of human OCD. However, intrigued scientists are looking in more detail at this gene in humans, hunting for variations in the DNA that might be tied to the development of the disorder.

Although it is currently unclear why mice lacking SAPAP3 developed symptoms, scientists are trying to determine what role SAPAP3 plays in the development of OCD. Scientists know that the SAPAP3 gene makes a protein that is involved in the regulation of the neurotransmitter glutamate. Glutamate is the most abundant neurotransmitter in the nervous system and plays a role in cognitive functions, such as learning and memory in the brain. Because nerve cells use neurotransmitters such as glutamate and serotonin to convey information from one cell to another, and therefore from one brain region to another, even small changes to the neurotransmitter systems can have profound consequences. The strong localization of the SAPAP3 protein in normal mice to a brain region called the striatum, suggested to Dr. Feng and his colleagues that the SAPAP3 protein might be important to regulating glutamate signals in this brain region. They went on to show that indeed, without SAPAP3, the connections between the striatum and the cortex of the brain were disrupted. They hypothesize that it is this disrupted brain circuit that is at least partially responsible for the OCD-like symptoms in their mice.

A Promising Future

While there are treatments for people with OCD, some people do not respond as well to current treatments as others do. Therefore, researchers are continuing to investigate the disorder and its biological cause(s) so that better treatments can be developed. In addition to providing insight into the biology behind OCD, researchers hope that the fortuitous discovery of SAPAP3 mice will facilitate the development of new drug therapies for OCD. Dr Feng found that the anxious SAPAP3 mice responded well to an SSRI drug commonly prescribed to humans with OCD; they had reduced grooming behavior and anxiety. These results are promising because they raise the possibility that novel drug therapies tested in these mice might also be beneficial for humans with OCD.

–Christine L. Nguyen and Kelly A. Dakin, Harvard Medical School

For More Information:

National Institutes of Health News: Gene Triggers Obsessive-Compulsive Disorder-Like Syndrome in Mice:
< http://www.nih.gov/news/pr/aug2007/nimh-22.htm >

National Institutes of Mental Health: Information on Obsessive Compulsive Disorder::
< http://www.nimh.nih.gov/healthinformation/ocdmenu.cfm >

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