Regulation of striatal dopamine responsiveness by Notch/RBP-J signaling.
Regulation of striatal dopamine responsiveness by Notch/RBP-J signaling.
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DOI：
10.1038/tp.2017.21
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发表时间：
2017-03-07
影响因子：
6.8
通讯作者：
Tanigaki K
中科院分区：
文献类型：
--
作者：
Toritsuka M;Kimoto S;Muraki K;Kitagawa M;Kishimoto T;Sawa A;Tanigaki K
多巴胺信号对奖赏学习和与恐惧相关的学习至关重要，并被认为与神经精神疾病有关。然而，调节多巴胺反应性的分子机制尚不清楚。在这里，我们展示了Notch/RBP-J信号在调节纹状体中的多巴胺反应中的关键作用。Noch/RBP-J信号调节成年中枢神经系统中各种神经细胞的命运和神经元功能。在神经细胞中有条件地删除RBP-J会导致对非选择性多巴胺激动剂阿朴吗啡和D1激动剂SKF38393的反应增强，并损害多巴胺依赖的工具性回避学习，这可被D1拮抗剂SCH23390纠正。RBP-J缺乏显著减少了纹状体中多巴胺的释放，并导致多巴胺能神经元的数量轻微减少。慢病毒介导的基因转移实验表明，纹状体RBP-J缺陷足以弥补这些缺陷。这些发现表明，Notch/RBP-J信号调节纹状体中的多巴胺反应，这可能解释了Notch/RBP-J信号影响个体对神经精神疾病的易感性的机制。
Dopamine signaling is essential for reward learning and fear-related learning, and thought to be involved in neuropsychiatric diseases. However, the molecular mechanisms underlying the regulation of dopamine responsiveness is unclear. Here we show the critical roles of Notch/RBP-J signaling in the regulation of dopamine responsiveness in the striatum. Notch/RBP-J signaling regulates various neural cell fate specification, and neuronal functions in the adult central nervous system. Conditional deletion of RBP-J specifically in neuronal cells causes enhanced response to apomorphine, a non-selective dopamine agonist, and SKF38393, a D1 agonist, and impaired dopamine-dependent instrumental avoidance learning, which is corrected by SCH23390, a D1 antagonist. RBP-J deficiency drastically reduced dopamine release in the striatum and caused a subtle decrease in the number of dopaminergic neurons. Lentivirus-mediated gene transfer experiments showed that RBP-J deficiency in the striatum was sufficient for these deficits. These findings demonstrated that Notch/RBP-J signaling regulates dopamine responsiveness in the striatum, which may explain the mechanism whereby Notch/RBP-J signaling affects an individual's susceptibility to neuropsychiatric disease.