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Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities

Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
Molecular Psychiatry (Impact Factor: 15.15). 10/2008; 15(2):177-84. DOI: 10.1038/mp.2008.97
Source: PubMed

ABSTRACT Mutations in SLITRK1 are found in patients with Tourette's syndrome and trichotillomania. SLITRK1 encodes a transmembrane protein containing leucine-rich repeats that is produced predominantly in the nervous system. However, the role of this protein is largely unknown, except that it can modulate neurite outgrowth in vitro. To clarify the role of Slitrk1 in vivo, we developed Slitrk1-knockout mice and analyzed their behavioral and neurochemical phenotypes. Slitrk1-deficient mice exhibited elevated anxiety-like behavior in the elevated plus-maze test as well as increased immobility time in forced swimming and tail suspension tests. Neurochemical analysis revealed that Slitrk1-knockout mice had increased levels of norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylglycol. Administration of clonidine, an alpha2-adrenergic agonist that is frequently used to treat patients with Tourette's syndrome, attenuated the anxiety-like behavior of Slitrk1-deficient mice in the elevated plus-maze test. These results lead us to conclude that noradrenergic mechanisms are involved in the behavioral abnormalities of Slitrk1-deficient mice. Elevated anxiety due to Slitrk1 dysfunction may contribute to the pathogenesis of neuropsychiatric diseases such as Tourette's syndrome and trichotillomania.

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    • "Parallèlement, l'expression du SLITRK1 a été confirmée dans les circuits striataux et corticaux, ce qui concorderait avec les régions impliquées dans la pathologie du SGT (Stillman et al., 2009). Un modèle animal a démontré une carence du gène SLITRK1 et une altération du phénotype associé à l'activité noradrénergique dans le SGT (Katayama et al., 2010). Cependant, l'expression du gène SLITRK1 dans le SGT demeure hypothétique étant donné que d'autres recherches n'ont pas été en mesure de reproduire ces résultats chez l'humain (Scharf et al., 2008). "
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    • "In addition, Kajiwara, Buxbaum, and Grice (2009) reported that the regulation of neurite outgrowth , as described by Aruga and Mikoshiba (2003) is mediated by binding to 14-3-3 molecules. Finally, Katayama et al. (2010) reported increased noradrenergic neurotransmission in a SLITRK1 mouse knockout that showed manifested an anxiety phenotype. A particularly interesting result reported recently by Shmelkov et al. (2010) was the observation of excessive grooming, responsive to agents that treat obsessive compulsive disorder in a mouse knockout of the closely related molecule, SLITRK5. "
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    • "SLITRK1 expression was confirmed in cortical striatal circuits, which is consistent with regions implicated in GTS pathology (Stillman et al., 2009). An animal model of SLITRK1 deficiency shows altered noradrenergic function phenotype related to alpha-agonists, which are used in the treatment of Tourette syndrome (Katayama et al., 2010). However, the SLITRK1 gene expression in GTS remain under question since other research was not able to replicate these results in human (Scharf et al., 2008). "
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