Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice

Sergey V. Shmelkov, Adília Hormigo, Deqiang Jing, Catia C. Proenca, Kevin G. Bath, Till Milde, Evgeny Shmelkov, Jared S. Kushner, Muhamed Baljevic, Iva Dincheva, Andrew J. Murphy, David M. Valenzuela, Nicholas W. Gale, George D. Yancopoulos, Ipe Ninan, Francis S. Lee, Shahin Rafii

Research output: Contribution to journalArticle

188 Scopus citations

Abstract

Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of obsessive thoughts and repetitive compulsive actions, and it often encompasses anxiety and depressive symptoms. Recently, the corticostriatal circuitry has been implicated in the pathogenesis of OCD. However, the etiology, pathophysiology and molecular basis of OCD remain unknown. Several studies indicate that the pathogenesis of OCD has a genetic component. Here we demonstrate that loss of a neuron-specific transmembrane protein, SLIT and NTRK-like protein-5 (Slitrk5), leads to OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors, and is alleviated by the selective serotonin reuptake inhibitor fluoxetine. Slitrk5/mice show selective overactivation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology and alterations in glutamate receptor composition, which contribute to deficient corticostriatal neurotransmission. Thus, our studies identify Slitrk5 as an essential molecule at corticostriatal synapses and provide a new mouse model of OCD-like behaviors.

Original languageEnglish (US)
Pages (from-to)598-602
Number of pages5
JournalNature Medicine
Volume16
Issue number5
DOIs
StatePublished - May 1 2010

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Shmelkov, S. V., Hormigo, A., Jing, D., Proenca, C. C., Bath, K. G., Milde, T., Shmelkov, E., Kushner, J. S., Baljevic, M., Dincheva, I., Murphy, A. J., Valenzuela, D. M., Gale, N. W., Yancopoulos, G. D., Ninan, I., Lee, F. S., & Rafii, S. (2010). Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice. Nature Medicine, 16(5), 598-602. https://doi.org/10.1038/nm.2125