Cry1Δ11 mutation induces ADHD-like symptoms through hyperactive dopamine D1 receptor signaling.
Cry1Δ11 mutation induces ADHD-like symptoms through hyperactive dopamine D1 receptor signaling.
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DOI：
10.1172/jci.insight.170434
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发表时间：
2023-08-22
期刊：
影响因子：
8
通讯作者：
Li, Jia-Da
中科院分区：
文献类型：
--
作者：
Liu, Dengfeng;Xie, Zhengyu;Gu, Panyang;Li, Xiangyu;Zhang, Yichun;Wang, Xinying;Chen, Zhiheng;Deng, Suixin;Shu, Yousheng;Li, Jia-Da
注意力缺陷多动障碍(ADHD)是一种高度遗传性的神经发育障碍，影响大约5.3%的儿童和大约2.5%的成年人。ADHD和睡眠障碍之间有密切的关系。具体地说，个体携带核心昼夜节律基因CRY1(c.1657+3A>；C)的突变，导致CRY1蛋白(CRY1Δ11)外显子11的表达缺失，导致他们表现出典型的多动症症状。然而，潜在的机制仍然难以捉摸。在这项研究中，我们证明了Cry1Δ11(c.1717+3A>；C)小鼠表现出类似多动症的症状，包括多动、冲动和学习和记忆障碍。在Cry1Δ11小鼠伏隔核内发现了一条高活性的cAMP信号通路。我们进一步证明，上调的c-Fos主要定位于NAC内表达多巴胺D_1受体的中棘神经元(DRD_1-MSN)。Δ11小鼠NAc中DRD1MSN的神经元兴奋性显著高于WT对照组。与WT CRY1蛋白相比，CRY1DRY11蛋白不能与GΔS蛋白相互作用并抑制α信号转导。最后，DRd1拮抗剂SCH23390使Cry1Δ11小鼠的大多数类似多动症的症状恢复正常。因此，我们的结果揭示了过度活跃的Δ信号是由高度流行的CRY1CRY11突变引起的ADHD的潜在机制和治疗靶点。
Attention-deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder that affects approximately 5.3% of children and approximately 2.5% of adults. There is an intimate relationship between ADHD and sleep disturbance. Specifically, individuals carry a mutation in the core circadian gene CRY1 (c. 1657 + 3A > C), which results in the deletion of exon 11 expression in the CRY1 protein (CRY1Δ11), causing them to exhibit typical ADHD symptoms. However, the underlying mechanism is still elusive. In this study, we demonstrate that Cry1Δ11 (c. 1717 + 3A > C) mice showed ADHD-like symptoms, including hyperactivity, impulsivity, and deficits in learning and memory. A hyperactive cAMP signaling pathway was found in the nucleus accumbens (NAc) of Cry1Δ11 mice. We further demonstrated that upregulated c-Fos was mainly localized in dopamine D1 receptor-expressing medium spiny neurons (DRD1-MSNs) in the NAc. Neuronal excitability of DRD1-MSNs in the NAc of Cry1Δ11 mice was significantly higher than that of WT controls. Mechanistically, the CRY1Δ11 protein, in contrast to the WT CRY1 protein, failed to interact with the Gαs protein and inhibit DRD1 signaling. Finally, the DRD1 antagonist SCH23390 normalized most ADHD-like symptoms in Cry1Δ11 mice. Thus, our results reveal hyperactive DRD1 signaling as an underlying mechanism and therapeutic target for ADHD induced by the highly prevalent CRY1Δ11 mutation.
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影响因子：
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