The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development
The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development
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DOI：
10.1038/mp.2012.29
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发表时间：
2012-09-01
影响因子：
11
通讯作者：
Bally-Cuif, L.
中科院分区：
文献类型：
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作者：
Lange, M.;Norton, W.;Bally-Cuif, L.
注意缺陷/多动障碍（ADHD）是一种以注意力不集中、多动、冲动增加和情绪失调为特征的神经发育障碍。通过连锁分析和精细定位，确定了亲Latrophilin 3 （LPHN3）基因编码的变异，这是一种假定的黏附- g蛋白偶联受体，是ADHD的一个危险因素。为了验证LPHN3与ADHD之间的联系，并了解LPHN3在该疾病的病因学中的功能，我们在斑马鱼发育过程中检测了其同源基因lphn3.1。lphn3.1功能的丧失导致腹侧间脑多巴胺阳性神经元的减少和错位，以及过度活跃/冲动运动表型。行为表型可以通过ADHD治疗药物哌甲酯和阿托西汀来挽救。综上所述，我们的研究结果表明Lphn3活性的降低与引发adhd样行为有关，并证明了其对大脑多巴胺能回路发育的相关贡献。
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, increased impulsivity and emotion dysregulation. Linkage analysis followed by fine-mapping identified variation in the gene coding for Latrophilin 3 (LPHN3), a putative adhesion-G protein-coupled receptor, as a risk factor for ADHD. In order to validate the link between LPHN3 and ADHD, and to understand the function of LPHN3 in the etiology of the disease, we examined its ortholog lphn3.1 during zebrafish development. Loss of lphn3.1 function causes a reduction and misplacement of dopamine-positive neurons in the ventral diencephalon and a hyperactive/impulsive motor phenotype. The behavioral phenotype can be rescued by the ADHD treatment drugs methylphenidate and atomoxetine. Together, our results implicate decreased Lphn3 activity in eliciting ADHD-like behavior, and demonstrate its correlated contribution to the development of the brain dopaminergic circuitry.