Cry1Δ11 mutation induces ADHD-like symptoms through hyperactive dopamine D1 receptor signaling
Dengfeng Liu, Zhengyu Xie, Panyang Gu, Xiangyu Li, Yichun Zhang, Xinying Wang, Zhiheng Chen, Suixin Deng, Yousheng Shu, Jia-Da Li
Dengfeng Liu, Zhengyu Xie, Panyang Gu, Xiangyu Li, Yichun Zhang, Xinying Wang, Zhiheng Chen, Suixin Deng, Yousheng Shu, Jia-Da Li
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Research Article Neuroscience

Cry1Δ11 mutation induces ADHD-like symptoms through hyperactive dopamine D1 receptor signaling

Abstract

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.

Authors

Dengfeng Liu, Zhengyu Xie, Panyang Gu, Xiangyu Li, Yichun Zhang, Xinying Wang, Zhiheng Chen, Suixin Deng, Yousheng Shu, Jia-Da Li

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Figure 5

Hyperactive DRD1 signaling in Cry1Δ11 mice.

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Hyperactive DRD1 signaling in Cry1Δ11 mice. (A and B) Representative imm...
(A and B) Representative immunofluorescence images and quantification of neurons expressing both c-Fos and DRD1 in the NAc of WT and Cry1Δ11 mice taken during ZT14–16. Scale bar: 10 μm. Data are presented as mean ± SEM. n = 5 mice/genotype, Genotype F (1, 16) = 33.40; ****P < 0.0001, 2-way ANOVA followed by Bonferroni’s t test. (C) The frequency of action potentials of DRD1-MSNs in the NAc induced by 400-pA current steps was significantly higher in Cry1Δ11 mice. Data are presented as mean ± SEM; n = 10–11 mice/genotype; *P < 0.05, repeated-measure ANOVA test. (D) Representative action potentials of DRD1-MSNs in NAc induced by 150-pA current steps. (E) The resting membrane potential of DRD1-MSNs in the NAc taken from Cry1Δ11 mice was significantly more depolarized than that of WT mice. Data are presented as mean ± SEM. n = 10 neurons from 10 WT mice, and n = 11 neurons from 10 Cry1Δ11 mice. *P < 0.05, unpaired 2-tailed Student’s t test. (F) Cry1Δ11 failed to inhibit DRD1-signaling, in contrast to the inhibition produced by WT Cry1, as demonstrated by a luciferase assay. Data are presented as mean ± SEM; n = 3; ***P < 0.001, unpaired 2-tailed Student’s t test. RLU, relative luminescence units. (G) In contrast to WT Cry1, Cry1Δ11 lost the ability to interact with Gαs, as assayed by a co-IP assay. Abs against HA or FLAG were used to IP cell lysates, and the immune complexes were blotted with Ab against HA or FLAG, respectively. (H) Diagram depicting the mechanism underlying hyperactive DRD1 signaling induced by the Cry1Δ11 mutation.