A paper in the Aug. 23 issue of Nature confirms one belief about obsessive-compulsive disorder, but contradicts another one. The study confirms that abnormalities in the so-called corticostriatal circuit seem to underlie OCD, but suggest that contrary to common wisdom, problems with the neurotransmitter serotonin may not.

"Our study provides direct evidence that it is the glutamatergic transmission that is deficient in OCD," Guoping Feng told BioWorld Today.

The severity of OCD varies widely, from basically a nuisance disorder to debilitating disease. Affecting an estimated 2 percent of the population, OCD is one of the most common psychiatric disorders, but its neurobiological basis is nevertheless unknown.

Feng, an assistant professor of neurobiology at Duke University, is primarily interested in the molecular basis of synaptic communication. Specifically, he studies scaffolding proteins in the postsynaptic density, which is the receiving end of a given connection between two neurons.

But such research, Feng said, is actually fairly likely to lead to insights into behavior. The reason is that communication is in a very basic sense what sets neurons apart. Synaptic transmission, Feng said, is "critical" to neuronal function. "So if you disrupt synaptic functions, you will likely have abnormal behavior."

Feng and his group are slowly disrupting synaptic function one knockout protein at a time — and when they knocked out the scaffolding protein Sapap3, what they got was mice that had lesions on their face. And that, as Feng put it, led to a natural question:

"Why would a brain-specific protein lead to facial lesions?"

Control experiments showed that the skin of the knockouts appeared to be normal. Videotaping the animals, though, showed that their behavior was not: they groomed themselves, well, obsessively.

"Normal mice spend less than 10 percent of their time grooming themselves," Feng said. "These knockouts spent more than 30 percent of their time" grooming. Indeed, the animals were so determined to keep themselves clean that their sleep cycles were disrupted as well. "They keep waking up to groom themselves," unable to stop despite the fact that their grooming was damaging their skin.

Further behavioral studies by Feng and his team showed that Sapap3 knockouts were more anxious than their wild-type cousins. OCD in humans, too, is often accompanied by anxiety. The antidepressant Prozac (fluoxetine, from Indianapolis-based Eli Lilly and Co.), which also is used to treat OCD patients and helps about half of them, reduced the knockouts' obsessive grooming as well as their anxiety symptoms.

Despite the fact that fluoxetine affects the serotonin system, electrophysiology experiments told a different tale about which neurotransmitter system is important in causing the symptoms in the first place. Several types of glutamate receptors had altered transmission characteristics in the knockout mice.

The researchers also investigated which parts of the brain, in addition to which neurotransmitter system, are at the root of OCD. It is clear from brain imaging studies that the corticostriatal circuit, which sends signals from the cortex to movement planning areas, is abnormal in humans with obsessive-compulsive disorder. But in human studies it is impossible to tell whether such anatomical abnormalities are "the cause or the result of OCD," Feng said.

In their paper, Feng and his colleagues present strong evidence for the former: it is possible to reverse the obsessive grooming of knockouts by using a viral vector to selectively restore Sapap3 expression in the corticostriatal circuits.

Though the findings confirm the importance of the corticostriatal circuit in OCD, other anatomical findings in the paper are more surprising. Feng and his team found that Sapap3 expression is low in both the amygdala, a brain structure that has long been associated with anxiety through other experimental approaches. Feng said the results could mean that a lack of Sapap3 leads to disrupted communication from the amygdala.

Overall, he said, the research provides a new model for anxiety, and even sleep disorders, as well as OCD research. It also could spur the development of drugs that target the glutamate system for OCD. Feng said that although there are "very few studies as yet" about the role of the glutamate system in OCD, there has recently been some recent interest in the connection, and that "this study will add more attraction to testing this type of drug in the future."

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