Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys
Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys
复制标题
DOI：
10.1038/s41593-020-0661-3
复制
发表时间：
2020-07-06
影响因子：
25
通讯作者：
Minamimoto, Takafumi
中科院分区：
文献类型：
--
作者：
Nagai, Yuji;Miyakawa, Naohisa;Minamimoto, Takafumi
由设计药物特异性激活的化学遗传学技术——设计受体（DREADDs）可对细胞信号传导、神经元活动和行为进行远程可逆控制。尽管基于毒蕈碱的DREADDs与氯氮平-N -氧化物（CNO）的组合已被广泛使用，但CNO的动力学缓慢、代谢缺陷以及潜在的脱靶效应是需要改进的方面。在此，我们为基于毒蕈碱的DREADDs提供了一种新的高亲和力、选择性激动剂——去氯氯氮平（DCZ）。正电子发射断层扫描显示，DCZ在小鼠和猴子中都能选择性地结合并占据DREADDs。在小鼠和猴子中，低剂量的DCZ（每千克1或3微克）全身给药在数分钟内就能通过hM3Dq增强神经元活动。肌肉注射DCZ（每千克100微克）可在前额叶皮质表达hM4Di的猴子中可逆地诱导空间工作记忆缺陷。DCZ是一种强效、选择性、代谢稳定且作用迅速的DREADD激动剂，在小鼠和非人灵长类动物的多种应用中都很有用。去氯氯氮平（DCZ）是一种对使用非人灵长类动物和小鼠的研究具有广泛用途的化学遗传学激动剂。DCZ能快速且可逆地激活DREADDs，并且其结合可通过正电子发射断层扫描无创地可视化。
The chemogenetic technology designer receptors exclusively activated by designer drugs (DREADDs) afford remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities and potential off-target effects of CNO represent areas for improvement. Here, we provide a new high-affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 mu g per kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 mu g per kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents a potent, selective, metabolically stable and fast-acting DREADD agonist with utility in both mice and nonhuman primates for a variety of applications.Deschloroclozapine (DCZ) is a broadly useful chemogenetic agonist for studies using nonhuman primates and mice. DCZ rapidly and reversibly activates DREADDs, and its binding can be visualized noninvasively by positron emission tomography.