BioEd Online

Mice with some of the hallmarks of obsessive compulsive disorder (OCD) have been bred by knocking out a single gene. While the mouse model isn't a perfect mimic for the human condition, researchers hope it will shed new light on our understanding of this debilitating disorder.

Guoping Feng of Duke University Medical Center in Durham, North Carolina, and his colleagues stumbled upon the mice when investigating a 'relay station' in the brain called the striatum — specifically, parts of neurons within this area that react to brain chemicals conveying messages from one neuron to another.

When researchers switched off a gene called Sapap3, which encodes the SAPAP3 protein, the mutant mice were more anxious than normal and compulsively groomed their faces, causing hair loss and skin wounds. SAPAP3 is highly expressed in the striatum, which collects instructions from the cortex and shuttles them out to other areas that help to carry out movements.

The team are confident that the behavioural changes are responsible for the wounds. "They could have been itchy, or had a skin condition," says Feng. But their grooming behaviour was the same before and after the lesions, he notes, and there was nothing abnormal about their skin or nerves. When the mice were given drugs used to treat OCD in humans — called selective serotonin reuptake inhibitors — their symptoms cleared up.

Injecting a trigger into the striatum of the mutant mice that turned their Sapap3 genes back on cured them of their compulsive behaviour. "What's most exciting for us is that you can put this gene back in a very small area and rescue the normal behaviour," Feng says. The team report their findings in Nature¹.

Of mice and men

Other psychiatric disorders have been modelled to a similar extent in animals. Earlier this month, a team led by Akira Sawa from Johns Hopkins University School of Medicine in Baltimore, Maryland, devised a mouse model of schizophrenia by knocking out a gene known to be linked to the disorder in humans². There are also other mouse models for OCD, though they all have limitations.

As yet, it is unclear how well this latest model translates into the human version of OCD, which can make people obsessively wash their hands or continuously worry about whether they left the stove on — to such an extent that the anxiety disrupts their lives. "There are no models of human psychiatric disorders that are full and satisfactory," says neurobiologist Steven Hyman of Harvard Medical School in Boston, Massachusetts, who has seen this study and groups it in with other 'imperfect' models. "There may never be."

Feng admits that it is hard, if not impossible, to come up with a perfect animal model for a human psychiatric condition, as no one knows what the animals are thinking. But the team still hopes that studying these mice can help develop better drugs for treating OCD in humans.

Feng's team is now studying human families where OCD is common to see if mutations in the Sapap3 gene are linked to OCD in humans as well as mice.

Keeping an open mind

Hyman thinks that studies such as Feng's, which start by looking at specific brain circuits rather than concentrating on one chemical, are the way forward.

Previous studies of OCD have pointed the finger at two other chemicals: serotonin and dopamine, but the current work highlights another: glutamate. This is the chemical that SAPAP3 proteins help synapses to sense. Few drugs targeting this chemical are on the market and a new mouse model for a disorder linked to glutamate could help researchers develop new treatments.

"The problem in psychiatric research is that people have developed serial neurotransmitter monotheism," Hyman says. If these researchers had started with an interest in a single neurotransmitter, he points out, they might never have made their discovery.