Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
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DOI：
10.1038/mp.2016.105
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发表时间：
2017-04-01
影响因子：
11
通讯作者：
Rubinstein, M.
中科院分区：
文献类型：
--
作者：
Bello, E. P.;Casas-Cordero, R.;Rubinstein, M.
运动执行和规划受到基底神经节回路中多巴胺D1和D2受体的严格调节。尽管已知刺激D1受体可增强运动功能，但D2受体（D2 R）刺激或阻断的整体效应仍存在高度争议，研究显示运动活动增加、减少或无变化。此外，阻断或消除D2 R的药理学和遗传学尝试导致了有争议的结果，质疑D2 R在运动功能中的重要性。在这项研究中，我们产生了一种可诱导的Drd 2空等位基因小鼠品系，它规避了组成型Drd 2（-/-）小鼠中发现的发育补偿，并使我们能够直接评估D2 R在自发运动活动和运动学习中的参与。我们已经发现，成年期D2 R的缺失会导致严重的运动障碍，包括运动功能减退、运动协调缺陷、新运动常规学习受损和自发性紧张症。此外，当在老年小鼠中诱导突变时，严重的运动障碍、静止性震颤和异常步态和姿势，使人联想到帕金森病的表型是明显的。总之，这里研究的条件性Drd 2敲除模型揭示了D2 R在运动功能中的总体基本贡献，并解释了D2 R阻滞剂在神经和精神疾病中使用时引起的一些副作用，包括精神分裂症，双相情感障碍，抽动秽语综合征，痴呆，酒精诱导的妄想和强迫症。
Motor execution and planning are tightly regulated by dopamine D1 and D2 receptors present in basal ganglia circuits. Although stimulation of D1 receptors is known to enhance motor function, the global effect of D2 receptor (D2R) stimulation or blockade remains highly controversial, with studies showing increasing, decreasing or no changes in motor activity. Moreover, pharmacological and genetic attempts to block or eliminate D2R have led to controversial results that questioned the importance of D2R in motor function. In this study, we generated an inducible Drd2 null-allele mouse strain that circumvented developmental compensations found in constitutive Drd2(-/-)mice and allowed us to directly evaluate the participation of D2R in spontaneous locomotor activity and motor learning. We have found that loss of D2R during adulthood causes severe motor impairments, including hypolocomotion, deficits in motor coordination, impaired learning of new motor routines and spontaneous catatonia. Moreover, severe motor impairment, resting tremor and abnormal gait and posture, phenotypes reminiscent of Parkinson's disease, were evident when the mutation was induced in aged mice. Altogether, the conditional Drd2 knockout model studied here revealed the overall fundamental contribution of D2R in motor functions and explains some of the side effects elicited by D2R blockers when used in neurological and psychiatric conditions, including schizophrenia, bipolar disorder, Tourette's syndrome, dementia, alcohol-induced delusions and obsessive-compulsive disorder.