Researchers at the Ansary Stem Cell Institute and the Department of Psychiatry at Weill Cornell Medical College discovered that mice missing a single gene developed repetitive obsessive-compulsive-like behaviors. The genetically altered mice, which behaved much like people with a certain type of obsessive-compulsive disorder (OCD), could help scientists design new therapies for this debilitating condition.
The researchers made this serendipitous discovery while looking at the role of a gene, called Slitrk5, which they had earlier linked to blood stem cells and vascular cells. In the April 25 online edition of Nature Medicine they report how, in follow-up studies, mice in which the gene was disabled ("knocked-out") demonstrated obsessive self-grooming and extreme anxiety. Further study showed that the frontal lobe-to-striatum circuitry of the brains of these mice were altered in the same ways that are implicated in OCD in humans.
This discovery links Slitrk5 to development of OCD-like behaviors, and offers scientists a new mouse model of the disorder, say the study's senior co-investigators, Dr. Shahin Rafii and Dr. Francis S.Y. Lee. Dr. Rafii is director of the Ansary Stem Cell Institute and professor in genetic medicine Weill Cornell Medical College and and an HHMI investigator. Dr. Lee is associate professor of psychiatry and pharmacology at the Medical College.
"Overall, our data suggest that Slitrk5 may have a central role in the development of the core symptoms of OCD -- self-injurious, repetitive behavior and increased anxiety," Dr. Rafii says. "Very few psychiatric disorders have been linked to a single gene, and it will be important to find out if patients with the disorder have an alteration of Slitrk5."
The findings may help scientists better understand both development and treatment for one or more of the several different types of human OCD behaviors, say Drs. Sergey Shmelkov and Adília Hormigo, the study's co-lead authors and members of the Ansary Stem Cell Institute. Dr. Shmelkov is an assistant research professor of genetic medicine, and Dr. Hormigo is an assistant professor of neurology at Weill Cornell Medical College and a neurologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
"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," says Dr. Lee. "But our finding of altered brain functioning suggests a very strong link at this point to some of the issues seen in humans."
The research team cannot say why a gene found in blood stem cells and vascular cells could be implicated in a behavioral brain disorder, but they speculate that "cross-talk" between the vascular system in the brain and neurons in brain tissue may be the link.
Dr. Rafii and his colleagues had previously identified Slitrk5 in the progenitor stem cells that create blood, and they subsequently demonstrated that the protein created by this gene is expressed in leukemia, embryonic stem cells, and in subsets of endothelial cells, which are the basic building blocks for the circulatory system.
In this study, the researchers were looking at the effects created when the Slitrk5 gene was "knocked out" in laboratory mice and replaced with a "reporter" gene. "We did this because we wanted to look at the effect on the blood system, which is what we are primarily interested in," says Dr. Shmelkov. "But we didn't find anything, which was frustrating."