Perry-Hauser Nicole A, Torres-Herraez Arturo, Boumhaouad Siham, Makowicz Emily A, Lowes Daniel C, Jin Michelle, Denny Christine A, Sulzer David, Mosharov Eugene V, Kellendonk Christoph, Javitch Jonathan A
Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
bioRxiv. 2025 Aug 1:2025.07.31.667389. doi: 10.1101/2025.07.31.667389.
Dopaminergic signaling is essential for regulating movement, learning, and reward. Disruptions in this system are linked to neuropsychiatric disorders such as ADHD. ADGRL3, an adhesion G protein-coupled receptor highly expressed in the brain, is genetically associated with increased ADHD risk. knockout in animals alters expression of dopaminergic markers and induces dopamine-related behavioral changes. However, its precise role in modulating dopamine signaling remains unclear. We investigated how knockout affects striatal dopamine release in mice using fast-scan cyclic voltammetry and fiber photometry with a dopamine sensor. measurements showed increased electrically-evoked dopamine release across the striatum. Conversely, recordings revealed reduced task-induced dopamine signals in the nucleus accumbens during an operant fixed interval task. This reduction was not due to impaired dopamine availability, as amphetamine-evoked release was unchanged. These findings suggest ADGRL3 modulates dopamine release in complex ways via different pre- and postsynaptic mechanisms.
多巴胺能信号传导对于调节运动、学习和奖赏至关重要。该系统的紊乱与诸如注意力缺陷多动障碍（ADHD）等神经精神疾病有关。ADGRL3是一种在大脑中高度表达的粘附G蛋白偶联受体，在基因上与ADHD风险增加相关。在动物中敲除该基因会改变多巴胺能标记物的表达并诱导与多巴胺相关的行为变化。然而，其在调节多巴胺信号传导中的精确作用仍不清楚。我们使用快速扫描循环伏安法和带有多巴胺传感器的光纤光度法研究了敲除ADGRL3如何影响小鼠纹状体多巴胺释放。测量结果显示，整个纹状体中电诱发的多巴胺释放增加。相反，在操作性固定间隔任务期间，光纤光度法记录显示伏隔核中任务诱导的多巴胺信号减少。这种减少并非由于多巴胺可用性受损，因为苯丙胺诱发的释放没有变化。这些发现表明，ADGRL3通过不同的突触前和突触后机制以复杂的方式调节多巴胺释放。
