Mice Provide Important Clues To Obsessive-compulsive Disorder

Duke University Medical Center investigators, in their basic research into how individual brain cells communicate with each other, discovered serendipitously that mice with a genetic mutation that prevents their brain cells from producing one key protein exhibited OCD-like behavior.

The finding may have uncovered important clues about a possible mechanism for OCD, a debilitating psychiatric condition affecting up to 2 percent of the world's people.

The international team of researchers, led by Duke molecular geneticist Guoping Feng, Ph.D., reported its findings in the August 23 issue of the journal Nature. The research was supported by the National Institutes of Health, the McKnight Endowment Fund for Neuroscience, and the Hartwell Foundation.

"The mice that could not produce this protein exhibited behaviors similar to that of humans with OCD, a compulsive action coupled with increased anxiety," Feng said. "We obviously cannot talk to mice to find out what they are thinking, but these mutant mice clearly did things that looked like OCD."

OCD is one of the most common psychiatric disorders in the world. It is marked by persistent intrusive thoughts (the obsession), repetitive actions (the compulsion) and anxiety. The severity OCD varies widely from person to person, and while the neurobiological basis of the disease is unknown, there are indications that genetics play a role, Feng said.

In their experiments, the Duke team focused on a portion of the brain known as the striatum, an area that controls the planning and execution of movement, as well as other cognitive functions. It is in many ways "the decider." In normal brains, a protein known as SAPAP3 is crucial for nerve signals to travel from one nerve cell to another across the synapse, the gap between the cells.

"This protein is important for allowing messages to cross synapses, and it is produced at high levels in the cells that make up the striatum," Feng explained. "When we looked closely at the brain cells of these mutant mice, we found that there were defects in the synapses.

"When we returned the protein into the striatum of brains of the mutant mice, the synaptic defects were repaired and their OCD-like behaviors subsided," Feng continued. "This is the first direct evidence that a synaptic defect in the striatum caused these OCD-like behaviors."

The researchers also found that a class of drugs known as selective serotonin reuptake inhibitors (SSRI) reduced the anxiety levels and suppressed the over-grooming in the mutant mice, further suggesting that what they observed in mice may also be analogous to human OCD. Serotonin, like SAPAP3, is one of many neurotransmitters, chemicals involved in nerve cell communication.

While SSRIs are the most commonly prescribed drug for humans with OCD, they are only effective for about half the patients, suggesting to Feng that many pathways involving different neurotransmitters are likely involved.

Feng and other colleagues at Duke are currently looking for additional gene variations that may affect how nerve signals cross synapses, and they are also beginning studies to determine if the gene mutant they discovered in mice plays a role in humans with OCD.

For this study, Feng collaborated with William Wetsel and Nicole Calakos from Duke University; Richard Weinberg from University of North Carolina at Chapel Hill; Serena Dudek from the National Institute of Environmental Health Sciences; as well as researchers from Zhejiang University School of Medicine, China; University of Coimbra, Portugal; and Gulbenkian Science Institute, Portugal.