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

• Published in: Nature medicine Vol. 16; no. 5; pp. 598 - 602
• Main Authors: Lee, Francis S, Rafii, Shahin, Shmelkov, Sergey V, Hormigo, Adília, Jing, Deqiang, Proenca, Catia C, Bath, Kevin G, Milde, Till, Shmelkov, Evgeny, Kushner, Jared S, Baljevic, Muhamed, Dincheva, Iva, Murphy, Andrew J, Valenzuela, David M, Gale, Nicholas W, Yancopoulos, George D, Ninan, Ipe
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2010; Nature Publishing Group
• Subjects: 631/378/548; 692/420; 692/699/476; Anatomy; Animals; Behavior, Animal; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell morphology; Compulsive Behavior - genetics; Development and progression; Etiology; Grooming; Health aspects; Infectious Diseases; letter; Membrane proteins; Membrane Proteins - deficiency; Membrane Proteins - genetics; Mental disorders; Metabolic Diseases; Mice; Mice, Knockout; Molecular biology; Molecular Medicine; Neostriatum - physiopathology; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Neural circuitry; Neurology; Neurosciences; Obsessive-compulsive disorder; Obsessive-Compulsive Disorder - diagnosis; Proteins; Psychological aspects; Rodents; Synapses; Synaptic Transmission; United States; Portugal
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2125

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.