A mouse model for OCD, OCD, OCD, OCD.......

What is it? -- Obsessive-compulsive disorder (OCD) is associated with repetitive functions, such as handwashing, counting and organizing things over and over again. Whereas an unaffected person might lock a door and know it is locked, a person with OCD is never sure and goes back to check over and over. OCD as a condition can interfere with normal life and those with severe OCD can’t hold down jobs. The causes of OCD and therefore the treatments remain unknown and/or very poorly tested.

By switching off a single gene in mice, Howard Hughes Medical Institute (HHMI) researchers have created rodents that behave anxiously and fixate on grooming.

The genetically altered mice, which behave much like people with obsessive-compulsive disorder, could help scientists design new therapies for this debilitating condition. A physiscain-scientist, Shahin Rafii of Weill Cornell Medical College in New York City and his colleagues Francis Lee and Sergey Shmelkov came across a gene called slitrk5, which is turned on in blood stem, leukemic, and vascular cells, they found, but it's activity is highest in the brain.

To see if they could find out more about slitrk5’s function, the researchers took the 'knockout'-approach and developed mice that completely lacked the gene. When the mice reached about three months of age, people began to notice that they seemed extremely anxious. They spent less time in open spaces or in high places and preferred corners or enclosed places more than mice typically do, and were extremely anxious and 'jumpy'.

Sore wounds and bald patches on the animals’ faces, were a sure giveaway of the animals’ intense and persistent preoccupation with self-grooming. The mice groomed themselves longer and more frequently than normal mice -- to the point that they lost fur and developed sores. The behavior recalls that of people with trichotillomania, a disease related to OCD in which people obsessively tug on their hair to the point that they pull it out.

Interestingly, Rafii and his colleagues found that treating the afflicted mice with Prozac (fluoxetine), which is a drug commonly prescribed to alleviate the symptoms of OCD in patients, ameliorated the excessive grooming.

Rafii’s team then collaborated with Lee and Adilia Hormigo of Weill Cornell, experts in molecular neuropsychiatry, on experiments that revealed patterns of activity in the animals’ brains that were strikingly similar to those in people with OCD. The orbitofrontal cortex, which sits in the front of the brain, behind the eyes, and contributes to decision-making, was unusually active in the mice. Functional imaging studies have shown that this area is hyperactive in patients with OCD, too. Notably, the earlier existing models of OCD didnt demonstrate the same kind of overactivation.

In addition, Rafii and his team found that in mice without slitrk5, a region deep in the brain called the striatum is smaller, forms less complex neural structures, and harbors fewer glutamate receptors than in normal mice. As a result, information does not appear to transmit well between the cortex and the striatum.

Predictably, Rafii now wants to know whether humans with OCD have mutations in the slitrk5 gene. His team has already begun searching for such mutations in the DNA of affected patients. If the search is successfull, we might have a proper understanding and optimistically, a possible cure of the dreaded condition.

Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive–like behaviors in mice.
Nature Medicine, Volume: 16, Pages: 598–602, 2010.