The protein Slitrk5—which is specific to neurons—is involved in the pathogenesis of obsessive–compulsive disorder (OCD) and loss of this protein leads to OCD-like behaviour in mice. The study, published in Nature Medicine, demonstrates that Slitrk5-knockout mice can be used as model of OCD and could help elucidate the molecular mechanisms that underlie this condition.
OCD is an anxiety disorder characterised by repetitive and obtrusive thoughts; this obsession leads to compulsive behaviour (e.g. handwashing or hoarding), which sufferers hopes will relieve their anxiety. Genetic analysis in humans has linked the gene SLITRK1 to Tourette’s syndrome—an OCD-like disorder—but the pathogenesis and genetics of OCD remain poorly understood.
Sergey Shmelkov and colleagues hypothesised that SLITRK5 (part of the same gene family as SLITRK1) could be involved in OCD-like behaviour and so they engineered a knockout mouse which lacked Slitrk5. The scientists observed that the Slitrk5-/- mice developed an anxiety-like behaviour and obsessively groomed, these mice had severe skin lesions and loss of facial hair that was not seen in wild-type mice. They found that fluoxetine—a selective serotonin reuptake inhibitor used in the treatment of OCD and also depression—relieved the compulsive behaviour in Slitkr5-knockout mice. The researchers then used anatomical, histological and functional analysis of the brains of Slitrk5-/- mice to further characterise their animal model of OCD. They recorded a number of observations in mice that lacked Slitkr5 compared to their wild-type counterparts: increased striatal volume, increased neural activity in the orbitofrontal cortex, abnormalities and changes to cell morphology in the striatum, decreased expression of glutamate receptors, and dysregulation of the corticostriatal circuitry.
Shmelkov et al. conclude that “Slitrk5 may have a central role in the development of OCD-like behaviour”. Some of the findings in this study are supported by existing data in humans (e.g. imaging studies imply that people with OCD have disruptions in corticostrial neurotransmission) but as yet no association with SLITRK5 has been found in humans. The investigators hope that their disease model of OCD can help investigate the pathogenesis and etiology of this prevalent anxiety disorder.
Shmelkov, S., Hormigo, A., Jing, D., Proenca, C., Bath, K., Milde, T., Shmelkov, E., Kushner, J., Baljevic, M., Dincheva, I., Murphy, A., Valenzuela, D., Gale, N., Yancopoulos, G., Ninan, I., Lee, F., & Rafii, S. (2010). Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive–like behaviors in mice Nature Medicine DOI: 10.1038/nm.2125