Knocking out a single gene in mice can produce symptoms of obsessive-compulsive disorder (OCD), researchers report in tomorrow's issue of Nature. Their experiments provide clues about the neural circuits and signaling pathways involved in compulsive behavior and may provide a useful animal model for studying OCD and evaluating treatments.
More than 2 million people in the United States suffer from OCD, which is characterized by intrusive, anxiety-provoking thoughts and repetitive behaviors meant to alleviate them--an obsessive fear of germs, for example, that leads to compulsive hand washing. Although drugs like Prozac, which increase levels of the neurotransmitter serotonin, seem to help some people, little is known about the mechanisms behind the disorder.
In the new study, neuroscientist Guoping Feng of Duke University in Durham, North Carolina, and colleagues, including Nicole Calakos and William Wetsel, didn't set out to tackle OCD per se. Feng studies proteins that form the synaptic connections between neurons, and his original goal was simply to see whether defects in such proteins could cause abnormal behavior. Indeed, when the researchers knocked out the gene for one synaptic protein, called SAPAP3, in mice they noticed something odd: After a few months, the animals developed lesions on their heads and necks.
At first, the researchers suspected a skin problem, but that wasn't the case. Cameras set up in the rodents' cages revealed that the knockout mice groomed their faces far more than normal mice do. The grooming was so excessive that the animals sometimes destroyed their eyes and ears. Additional behavioral tests suggested that the mutant mice were unusually anxious, another symptom of OCD. Both the anxiety and the excessive grooming were alleviated by Prozac.
Digging for the root of the problem, the team experimented with slices of brain from the mutant mice. This pointed to a defect in the striatum, part of a circuit involved in controlling actions. Some studies with human OCD patients have hinted at abnormal activity in this same circuit. In the knockout mice, at least, one problem is that synapses that respond to the neurotransmitter glutamate didn't transmit signals reliably.
The findings should spur research on the potential role of the striatum and glutamate synapses in human OCD, says Steven Hyman, a psychiatrist at Harvard University and former director of the National Institute of Mental Health (NIMH) in Bethesda, Maryland. The clue to glutamate, Hyman says, "reminds us of what we never should have forgotten"--that even though Prozac and other serotonin-modulating drugs can work, the underlying problem may lie elsewhere. The study may also lead to clues about the mysterious genetics of OCD, adds Husseini Manji, director of the Mood and Anxiety Disorders Program at NIMH. "I think you'll see a flurry of activity to look at this gene and its partners," Manji says.