Neuroscientist Guoping Feng and his colleagues had a simple plan. They would breed mice lacking a particular gene in order to probe the brain effects of the protein produced by that gene. To the scientists' surprise, they found that these gene-deprived animals provide a rudimentary rodent model of obsessive-compulsive disorder (OCD), a poorly understood psychiatric ailment that affects nearly 1 in 50 people.
The team, primarily from Duke University Medical Center in Durham, N.C., reports that mice missing this gene appear to be fine for their first 4 to 6 months. Then they begin to groom themselves excessively, which results in hair loss and skin injuries. They also display heightened anxiety. Compared with genetically intact mice, the gene-deprived animals are slower to enter and quicker to exit risky settings, such as open spaces.
The targeted gene makes a protein known as SAPAP3, which fosters brain-cell communication via the chemical messenger glutamate, especially in the striatum, a structure near the top of the brain stem. The striatum coordinates physical actions and guides the planning and control of behavior.
Further study of the gene for SAPAP3 and related genes in mice and people may lead to new drug treatments for OCD, Feng's team reports in the Aug. 23 Nature.
"We obviously cannot talk to mice to find out what they are thinking, but these mutant mice clearly did things that looked like OCD," Feng says.
The disease is characterized by unwanted intrusive thoughts that generate intense worry and result in repetitive behaviors aimed at quelling anxiety. Sufferers may wash their hands for hours every day for fear of becoming contaminated by germs or repeatedly check that doors are locked.
Prior studies of OCD have implicated disturbed communication among three areas of the brain: the thalamus, which relays sensory signals; the frontal cortex, which controls thoughts and behavior; and the striatum. Causes of this communication breakdown were unclear.
Video surveillance confirmed that mice without the gene for SAPAP3 slept fitfully and caused their own skin injuries by excessively grooming themselves. Administration of fluoxetine (Prozac) to the mutant mice for 6 days generally decreased excessive grooming, aided sleep, and eased signs of anxiety.
Doctors often prescribe Prozac and related medications for OCD. These drugs target the neurotransmitter serotonin and alleviate symptoms in about half of OCD patients, suggesting to Feng that various neurotransmitters contribute to the disorder.
Feng's analyses of neural tissue from mutant mice indicate that the lack of SAPAP3 suppresses activity in the striatum usually triggered by glutamate, and that this cutback stunts connections between the striatum and the cortex.
When the scientists injected the striata of 7-day-old mutant mice with a substance containing the gene for SAPAP3, the animals didn't develop grooming abnormalities or anxiety.
Feng's team provides an urgently needed model of OCD, remarks neuroscientist Ann M. Graybiel of the Massachusetts Institute of Technology. It remains unclear why deleting the gene for SAPAP3 produced only excessive grooming and anxiety, because brain circuits that include the striatum underlie a broad range of behaviors, Graybiel says.
Department of Neurobiology
Duke University Medical Center
Durham, NC 27710
Ann M. Graybiel
Massachusetts Institute of Technology
Department of Brain and Cognitive Sciences
43 Vassar Street, 46-6133
Cambridge, MA 02139
Steven E. Hyman
Department of Neurobiology
Harvard Medical School
Cambridge, MA 02138
Hyman, S.E. 2007. Obsessed with grooming. Nature 448(Aug. 23):871-872.