Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by obsessive thoughts, compulsive repetitive actions and, often, anxiety and depression. Its underlying causes and pathology remain largely unknown, although a genetic component has been suggested. Now, scientists have identified a gene whose absence causes OCD-like behavior in mice. The gene encodes Slitrk5, a neuron-specific transmembrane protein that is widely expressed throughout the central nervous system.

Shahin Rafii and Francis S.Y. Lee (Weill Cornell Medical College, New York, NY) directed the studies, which used genetically engineered mice lacking Slitrk5. From 3 months of age, these knockout mice began grooming themselves excessively, causing hair loss and skin lesions (Nat. Med. published online 25 April 2010; doi:10.1038/nm.2125). They also showed increased anxiety-like behaviors in various types of behavioral testing (elevated-plus maze, open-field test and marble-burying test). Compulsive behavior and anxiety are core symptoms of OCD in humans, leading the researchers to evaluate whether there were other similarities between people with OCD and the Slitrk5-knockout mice. The scientists treated the knockout mice with a selective serotonin reuptake inhibitor (SSRI), a common treatment for people with OCD. Administration of the SSRI fluoxetine prevented the compulsive behavior in Slitrk5-knockout mice.

Next, the research group examined brain activity in the knockout mice and found excessive neuronal activity in the orbitofrontal cortex. Notably, people with OCD show a similar increase in activity in this area of the brain, a characteristic that has not been recapitulated in existing mouse models of OCD. The scientists also found structural abnormalities in the striatum of the brain, a region associated with reward and decision-making, in the knockout mice. Neurons in the striatum were less complex in knockout mice than in wild-type mice.

Overall, these results suggest that Slitrk5 has a role in the development of OCD and OCD-like behaviors. Slitrk5-knockout mice could be useful in future studies investigating the pathogenesis of OCD. In addition, these mice may serve as a model of OCD for the development and assessment of potential therapies.

Rafii noted that few psychiatric disorders can be linked to a single gene and that it will be important to evaluate whether people with OCD have any alterations in SLITRK5. Furthermore, Lee warned, “We can't draw direct parallels between mice and humans, because OCD behavior in mice shows up as excessive self-grooming, and in humans there is a broad spectrum of behaviors, from hand-washing to other compulsive actions as well as obsessive thoughts.”