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New Insights into Obsessive-Compulsive Disorder
6 Sep, 2007 12:57 pm
Obsessive-compulsive disorder (OCD) is a common debilitating psychiatric disorder, yet the cause of OCD is unknown and few effective treatments are available. A recent study of mutant mice reveals a novel mechanism leading to OCD-like behaviors in mice and suggests potential new therapeutic strategies.
Obsessive-Compulsive Disorder (OCD) is an anxiety disorder characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions). OCD is one of the most common psychiatric disorders, affecting about 2 percent of the world population. Some of the most frequently occurring obsessive thoughts in OCD are of contamination, pathological doubt and a need for symmetry, while the most common compulsive behaviors include washing, checking and counting. Currently, the cause of OCD is unknown.
There are billions of neurons in the brain. They are connected in very specific ways and they constantly talk to each other. Defects in neuronal connections and communications have been widely implicated in neurological and neuropsychiatric disorders. We study how neurons in the brain make these specific connections and how they communicate with each other. In this study we focused on a gene called SAPAP3, which is critical for normal communication between neurons in the brain. The SAPAP3 gene is highly expressed in a brain region called the striatum, one of the brain's information processing and decision-making centers that control movement and related behaviors. Previous studies in OCD patients suggested that defects in the striatum may be involved in OCD, but the nature of the defects were unclear.
When we mutated the SAPAP3 gene in mice using a genetic technology called gene knockout, we found that the mutant mice exhibited compulsive grooming behavior leading to hair loss and skin lesions in the facial and neck areas. Continuous videotaping observations confirmed that the lesions were caused by excessive self-grooming. These mice also showed increased anxiety—they tend to stay in corners and hesitate to enter "risky" environments, such as a brightly lit area. This is consistent with an OCD-like behavior, since anxiety is often associated with OCD in humans. When we treated these mice with Prozac, the first line of medicine for treating OCD, both the compulsive grooming and anxiety in these mice were relieved.
Nerve cells in the brain use several chemical messengers to communicate with each other. Previous studies of OCD have focused on one of the messengers called serotonin. However, SAPAP3 is required for neuronal communications that use another messenger called glutamate. Examination of the brain of SAPAP3 mutant mice indeed revealed defects in communications mediated by glutamate in the striatum. To prove that these defects play a causal role in the OCD-like behavior in mice, we reinserted SAPAP3 selectively into the striatum of the mutant mice. This is sufficient to largely prevent the development of compulsive grooming, anxiety and facial lesions. Thus, these studies revealed a brain region as well as a new player (glutamate-mediated communication) in OCD-like behavior. The ultimate goal is to translate this new discovery into a better understanding of the pathology and causes of OCD, and into new, improved therapeutic targets for drug development.
Welch M., J., et al, Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice, Nature 448, 894-900, 23 August 2007