van der Veen Bastiaan, Kapanaiah Sampath K T, Kilonzo Kasyoka, Steele-Perkins Peter, Jendryka Martin M, Schulz Stefanie, Tasic Bosiljka, Yao Zizhen, Zeng Hongkui, Akam Thomas, Nicholson Janet R, Liss Birgit, Nissen Wiebke, Pekcec Anton, Kätzel Dennis
Institute of Applied Physiology, Ulm University, Ulm, Germany.
Allen Institute for Brain Science, Seattle, WA, USA.
Commun Biol. 2021 Jun 2;4(1):662. doi: 10.1038/s42003-021-02188-w.
Pathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of G-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among G-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest G-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.
病理性冲动是多种精神疾病的一种使人衰弱的症状，有效的治疗选择很少。为了识别具有抗冲动作用的可药物作用受体，我们开发了一种将行为化学遗传学和基因表达分析相结合的系统靶点发现方法。对小鼠前额叶皮质的三个亚区进行空间限制抑制，结果显示前扣带回皮质（ACC）调节过早反应，这是一种运动冲动形式。用设计受体探究三种G蛋白级联反应，我们发现ACC第5层锥体神经元（L5-PCs）中G信号的激活强烈、可重复且选择性地降低了挑战诱导的冲动性。对小鼠ACC细胞类型和402种GPCR进行差异基因表达分析，结果显示——在G偶联受体编码基因中——Grm2在L5-PCs中表达最具选择性，而其他靶点很少。通过验证我们的方法，我们证实了代谢型谷氨酸受体2（mGluR2）的激活减少了过早反应。这些结果表明ACC L5-PCs中的G偶联受体是冲动控制障碍的治疗靶点。
