Attention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder worldwide. Affected individuals present with hyperactivity, inattention, and cognitive deficits and display a characteristic paradoxical response to drugs affecting the dopaminergic system. However, the underlying pathophysiology of ADHD and how this relates to dopaminergic transmission remains to be fully understood. Sorcs2^−/− mice uniquely recapitulate symptoms reminiscent of ADHD in humans. Here, we show that lack of SorCS2 in mice results in lower sucrose intake, indicating general reward deficits. Using in-vivo recordings, we further find that dopaminergic transmission in the ventral tegmental area (VTA) is shifted towards a more regular firing pattern with marked reductions in the relative occurrence of irregular firing in Sorcs2^−/− mice. This was paralleled by abnormal acute behavioral responses to dopamine receptor agonists, suggesting fundamental differences in dopaminergic circuits and indicating a perturbation in the balance between the activities of the postsynaptic dopamine receptor DRD1 and the presynaptic inhibitory autoreceptor DRD2. Interestingly, the hyperactivity and drug response of Sorcs2^−/− mice were markedly affected by novelty. Taken together, our findings show how loss of a candidate ADHD-risk gene has marked effects on dopaminergic circuit function and the behavioral response to the environment.

注意缺陷多动障碍（ADHD）是世界范围内最常被诊断的神经发育障碍。受影响的个体表现为活动过度，注意力不集中和认知缺陷，并且对影响多巴胺能系统的药物表现出特征性的自相矛盾反应。但是，ADHD的潜在病理生理学及其与多巴胺能传递的关系尚待充分了解。Sorcs2 ^-/-小鼠独特地概括了让人联想到ADHD的症状。在这里，我们表明小鼠中缺乏SorCS2导致蔗糖摄入量降低，表明一般的奖励缺陷。使用体内记录，我们进一步发现，腹侧被盖区（VTA）中的多巴胺能传播朝着更规律的射击方式转移，在Sorcs2 ^-/-小鼠中不规则射击的相对发生率显着降低。这与对多巴胺受体激动剂的异常急性行为反应并行，这表明多巴胺能回路的根本差异，并表明突触后多巴胺受体DRD1和突触前抑制性自体受体DRD2活性之间的平衡受到干扰。有趣的是，Sorcs2 ^-/-小鼠明显受到新颖性的影响。综上所述，我们的研究结果表明候选ADHD风险基因的丢失如何对多巴胺能回路功能和对环境的行为响应产生显着影响。