Zebrafish Neurogenetics Group, Laboratory of Neurobiology and Development (N&D), CNRS UPR 3294, Institute of Neurobiology Alfred Fessard, Avenue de la Terrasse, Gif-sur-Yvette cédex, France.
Mol Psychiatry. 2012 Sep;17(9):946-54. doi: 10.1038/mp.2012.29. Epub 2012 Apr 17.
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.
注意缺陷多动障碍（ADHD）是一种神经发育障碍，其特征为注意力不集中、多动、冲动增加和情绪调节障碍。通过连锁分析和精细映射，发现编码拉普罗林 3（LPHN3）的基因变异是 ADHD 的一个风险因素，LPHN3 是一种假定的黏附 G 蛋白偶联受体。为了验证 LPHN3 与 ADHD 之间的联系，并了解 LPHN3 在疾病发病机制中的作用，我们在斑马鱼发育过程中检查了其同源物 lphn3.1。lphn3.1 功能缺失会导致腹侧间脑多巴胺阳性神经元减少和位置异常，并导致多动/冲动型运动表型。ADHD 治疗药物哌甲酯和托莫西汀可挽救这种行为表型。综上所述，我们的研究结果表明，Lphn3 活性降低会引发类似 ADHD 的行为，并证明其与脑多巴胺能回路发育相关。
