Obsessive compulsive disorder (OCD) is a psychiatric condition which is characterized by intrusive thoughts and ritualized and repetitive behaviours, such as excessive hand-washing, which are performed in order to neutralize the obsessions. OCD is one of a spectrum of disorders that includes Tourette’s Syndrome, autism and bipolar disorder.
OCD affects approximately 2% of the population, and is listed by the World Health Organization as being amongst the top 10 most debilitating illnesses, in terms of decreased quality of life and loss of income. It is often treated – only mildly effectively – with behaviour and cognitive therapies, or with medication such as specific serotonin reuptake inhibitors (SSRIs, one class of drugs, which includes Prozac, that is used to treat depression).
There is little research into the neurobiological bases of OCD, largely because there has, until now, been no animal model of the condition. In today’s issue of Nature, however, an international team of researchers, led by Guoping Feng of the Department of Neurobiology at Duke University Medical Center in Durham, North Carolina, describe a genetically engineered mouse that exhibits increased anxiety and compulsive behaviour.
Welsh, et al created and bred a strain of SAPAP3 knockout mice. That is, they created genetically engineered mice lacking the SAPAP3 gene. SAPAP3 is one of dozens of proteins that comprise the post-synaptic density, a complex network of proteins found in nerve cells at both sides of the synapse. This protein scaffold maintains the integrity of the synapse by, for example, positioning neurotransmitter receptors and mediating the recycling of synaptic vesicles.
The SAPAP3 protein is synthesized at high levels in neurons that are responsive to the excitatory neurotrnsmitter glutamate. It is expressed highly in only one region of the brain. This region, the striatum, had previously been implicated in OCD and related disorders – neuroimaging studies had indicated that these disorders are associated with abnormalities in the connections between the striatum and the frontal cortex.
Mice lacking the SAPAP3 gene appeared normal. They weighed the same as normal mice and were fertile, and anatomical and histological analyses showed no abnormalities in the brain.
At 4-6 months of age, however, the mice developed patches of hairless skin under the eyes and damaged skin around large parts of the head and neck (above). This was not the result of aggression between the animals, or of excessive grooming of each other, because the mice were not observed to behave aggressively, and the lesions developed both when they were housed alone or in groups.
Rather, videotaping of the animals’ behaviour showed that the lesions were self-injurious, and occurred as a result of excessive self-grooming. Mice lacking the SAPAP3 gene were found to groom themselves more often, and for longer, than normal mice. The mutant animals even groomed themselves during periods when they would normally be asleep.
The mice lacking the SAPAP3 gene also exhibited anxiety-like behaviour. When placed in an open and lit space, for example, they tended to avoid the central area, and instead remained close to the walls around the edges. And, when placed into a chamber divided into dark and well-lit areas, the animals took longer to cross into the well-lit areas than did normal mice, and spent less time there when they did eventually cross.
The excessive grooming exhibited by SAPAP3 knockout mice is similar to the compulsive behaviours characteristic of people with OCD. And fluoxetine (Prozac) was found to alleviate the animals’ excessive grooming and anxiety-like behaviours. Thus, the mice created for the study may prove to be a useful animal model for OCD.
However, this potential model cannot be used to investigate the unwanted, intrusive thoughts that are characteristic of people with OCD. Furthermore, it cannot be assumed that variations in the human form of this gene are involved in the condition. And even if the human version of the SAPAP3 gene is involved in OCD, the condition – and other psychiatric conditions – is likely to have at least several other genes associated with it.
Nevertheless, this study confirms the involvement of the frontal-striatal pathway in OCD and related disorders, and provides some insight into the cellular and molecular bases of the condition.
Welsh, J. M., et al. (2007). Cortico-striatal synaptic defects and OCD-like behaviours in SAPAP3-mutant mice. Nature 448: 894-900. [Abstract]