OCD linked to glutamate system

US researchers have created an obsessive-compulsive disorder (OCD)-like set of behaviours in mice and reversed them with antidepressants and genetic targeting of a key brain circuit.

Duke University researcher Dr Guoping Feng and colleagues bred mice without a specific gene, SAPAP3, and found defects in a brain circuit previously implicated in OCD.

Much like people with a form of OCD, the mice engaged in compulsive grooming, which led to bald patches with open sores on their heads. They also exhibited anxiety-like behaviours. When the missing gene was reinserted into the circuit, both the behaviors and the defects were largely prevented.

SAPAP3 makes a protein that helps brain cells communicate via the glutamate chemical messenger system.

"Since this is the first study to directly link OCD-like behaviours to abnormalities in the glutamate system in a specific brain circuit, it may lead to new targets for drug development," Feng said. "An imbalance in SAPAP3 gene-related circuitry could help explain OCD."

The study was published in the August 23 issue of Nature.

Previous studies of OCD had implicated a circuit in which the striatum, which straddles the middle of the brain, processes decisions by the cortex, the executive hub at the front of the brain. But exactly how circuit communications might go awry remained a mystery, and glutamate was not a prime suspect.

Nor were Feng and colleagues initially interested in OCD. Rather, they sought to understand the function of the protein made by the SAPAP3 gene, which is involved in glutamate-mediated communications in the cortex-striatum circuit. To find out how it worked, they used genetic engineering to generate SAPAP3 knockout mice.

The mice seemed normal at first, but after four to six months, all developed telltale bald patches of raw flesh on their faces, caused by compulsive scratching. Videotapes confirmed that the sores were self-inflicted.

"We were surprised by the magnitude of this phenomenon," Feng said. "The parallels with OCD were pretty striking."

In a series of behavioural tests, his team determined that the SAPAP3 knockout mice also showed anxiety-like behaviours, often associated with OCD. They were slower to venture into - and quicker to exit - risky environments.

And, like their human counterparts, the animals responded to treatment with a serotonin selective reuptake inhibitor (fluoxetine), which reduced both the excessive grooming and anxiety-like behaviors.

SAPAP3 is the only member of a glutamate-regulating family of proteins that is present in large amounts in the striatum. It is part of the machinery at the receiving end of the connections between brain cells, where the neurotransmitter binds to receptors, triggering increased activity among the cells.

The researchers found that lack of SAPAP3 genes dampened the increased activity usually caused by glutamate and stunted the development and functioning of circuit connections.

When the researchers injected the striatum of seven-day-old knockout mice with a probe containing the SAPAP3 gene, it protected them from developing the OCD and anxiety-like behaviours four to six months later and corrected the circuit dysfunction. This confirmed that the absence of the SAPAP3 gene in the striatum was indeed responsible for the OCD-like effects.

The findings suggest that anxiety-related behavior may stem from the striatum, which serves as a pivotal link between the cortex and emotion hubs. The researchers note that recent genetic studies of OCD have hinted at involvement of glutamate-related mechanisms. Feng's team is also looking beyond the SAPAP3 gene to other related genes in the circuit that could lead to similar behavioral problems. They are exploring how the SAPAP3 gene affects neural communications and how it works at the molecular level - with an eye to possible applications in drug development.

Source: US National Institutes of Health