From the Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Disorders and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
the Institute of Neuroscience, Soochow University, Suzhou City, Jiangsu 215123, China, and.
J Biol Chem. 2018 Apr 6;293(14):5090-5101. doi: 10.1074/jbc.RA117.000618. Epub 2018 Feb 15.
Abelson helper integration site 1 (AHI1) is associated with several neuropsychiatric and brain developmental disorders, such as schizophrenia, depression, autism, and Joubert syndrome. deficiency in mice leads to behaviors typical of depression. However, the mechanisms by which AHI1 regulates behavior remain to be elucidated. Here, we found that down-regulation of expression of the rate-limiting enzyme in dopamine biosynthesis, tyrosine hydroxylase (TH), in the midbrains of knockout (KO) mice is responsible for -deficiency-mediated depressive symptoms. We also found that Rev-Erbα, a transcriptional repressor and circadian regulator, is up-regulated in the KO mouse midbrains and -knockdown Neuro-2a cells. Moreover, brain and muscle Arnt-like protein 1 (BMAL1), the α transcriptional regulator, is also increased in the KO mouse midbrains and -knockdown cells. Our results further revealed that AHI1 decreases BMAL1/Rev-Erbα expression by interacting with and repressing retinoic acid receptor-related orphan receptor α, a nuclear receptor and transcriptional regulator of circadian genes. Of note, deficiency reversed the reduction in TH expression induced by deficiency. Moreover, microinfusion of the Rev-Erbα inhibitor SR8278 into the ventral midbrain of KO mice significantly increased TH expression in the ventral tegmental area and improved their depressive symptoms. These findings provide a mechanistic explanation for a link between AHI1-related behaviors and the circadian clock pathway, indicating an involvement of circadian regulatory proteins in AHI1-regulated mood and behavior.
Abelson helper 整合位点 1（AHI1）与多种神经精神和大脑发育障碍有关，如精神分裂症、抑郁症、自闭症和杰伯综合征。在小鼠中缺乏 AHI1 会导致典型的抑郁行为。然而，AHI1 调节行为的机制仍有待阐明。在这里，我们发现多巴胺生物合成限速酶酪氨酸羟化酶（TH）在敲除（KO）小鼠中表达下调，导致 - 缺乏介导的抑郁症状。我们还发现，Rev-Erbα，一种转录抑制因子和昼夜节律调节剂，在 KO 小鼠中脑和 - 敲低的 Neuro-2a 细胞中上调。此外，脑和肌肉芳香烃受体核转录因子样蛋白 1（BMAL1），α 转录调节因子，也在 KO 小鼠中脑和 - 敲低的细胞中增加。我们的结果进一步表明，AHI1 通过与视黄酸受体相关孤儿受体α相互作用并抑制其表达来降低 BMAL1/Rev-Erbα 的表达，视黄酸受体相关孤儿受体α是昼夜基因的核受体和转录调节剂。值得注意的是，- 缺乏逆转了 - 缺乏诱导的 TH 表达减少。此外，将 Rev-Erbα 抑制剂 SR8278 微注入 KO 小鼠的腹侧中脑，可显著增加腹侧被盖区的 TH 表达，并改善其抑郁症状。这些发现为 AHI1 相关行为与昼夜节律途径之间的联系提供了机制解释，表明昼夜调节蛋白参与了 AHI1 调节的情绪和行为。
