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

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 symptoms1,2. Recently, the corticostriatal circuitry has been implicated in the pathogenesis of OCD3,4. However, the etiology, pathophysiology and molecular basis of OCD remain unknown. Several studies indicate that the pathogenesis of OCD has a genetic component5–8. 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.

The Leucine-Rich Repeat Superfamily of Synaptic Adhesion Molecules: LRRTMs and Slitrks

“…Mutation of this serine residue to alanine was shown to abolish the interaction of Slitrk1 with 14-3-3 proteins, and block the induction of neurite outgrowth in cultured mouse neurons (Kajiwara et al, 2009). Studies using knockout mice have implicated Slitrk5 in the dendritic complexity of medium spiny neurons of the adult striatum (Shmelkov et al, 2010), and showed that Slitrk6 exerts trophic actions (Katayama et al, 2009). Slitrk6-knockout mice also exhibit marked cell death in the spiral and vestibular ganglia (Katayama et al, 2009).…”

“…Knockout mice have also been used recently to demonstrate the involvement of Slitrk3 and -5 in synapse formation (Shmelkov et al, 2010;Takahashi et al, 2012). In cultured neurons, Slitrk5 localizes to postsynaptic sites.…”

“…In cultured neurons, Slitrk5 localizes to postsynaptic sites. Genetic ablation of Slitrk5 results in abnormalities in striatal anatomy, and altered neuronal morphology and glutamate receptor composition in the striatum, which lead to inefficient corticostriatal neurotransmission (Shmelkov et al, 2010). Recently, Slitrk3 was shown to selectively localize to inhibitory synapses and trigger inhibitory Excitatory synapse formation and elimination via synaptic activity (de Wit et al, 2009;Ko et al, 2009;Linhoff et al, 2009)…”

“…These results lend support to a possible role of Slitrk1 in neuropsychiatric disorders. Slitrk5-null mice initially develop increased anxiety-like behaviors (evaluated by the open-field test) and display repetitive and excessive self-grooming behaviors (Shmelkov et al, 2010), that lead to the formation of severe facial skin lesions and hair loss. Chronic treatment with fluoxetine, a selective serotonin reuptake inhibitor, alleviated these characteristic phenotypes of Slitrk5-deficient mice.…”

“…These mice also exhibit anatomical deficits as well as abnormal neurotransmission in the striatum. In addition, they show overactivation of the orbitofrontal cortex, determined by measuring the levels of FosB protein, a transcription factor that is commonly used to assess neuronal activity (McClung et al, 2004;Shmelkov et al, 2010). Overall, Slitrk5-null mice recapitulate several key aspects of obsessivecompulsive disorder (OCD), suggesting that these mice might be an animal model for OCD.…”