Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
Mol Psychiatry. 2010 Feb;15(2):177-84. doi: 10.1038/mp.2008.97. Epub 2008 Sep 16.
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.
SLITRK1 基因突变可在抽动秽语综合征和拔毛癖患者中发现。SLITRK1 编码一种富含亮氨酸重复的跨膜蛋白，主要在神经系统中产生。然而，除了它可以在体外调节神经突生长之外，这种蛋白质的作用在很大程度上是未知的。为了阐明 Slitrk1 在体内的作用，我们开发了 Slitrk1 敲除小鼠，并分析了它们的行为和神经化学表型。Slitrk1 缺陷型小鼠在高架十字迷宫测试中表现出焦虑样行为增加，以及在强迫游泳和悬尾测试中不动时间增加。神经化学分析显示，Slitrk1 敲除小鼠的去甲肾上腺素及其代谢物 3-甲氧基-4-羟基苯乙二醇水平升高。α2-肾上腺素能激动剂可乐定可用于治疗抽动秽语综合征患者，其给药可减轻 Slitrk1 敲除小鼠在高架十字迷宫测试中的焦虑样行为。这些结果使我们得出结论，去甲肾上腺素能机制参与了 Slitrk1 敲除小鼠的行为异常。由于 Slitrk1 功能障碍引起的焦虑可能导致抽动秽语综合征和拔毛癖等神经精神疾病的发病机制。
