Department of Fetology, the First Affiliated Hospital of Soochow University, Suzhou, 215004, People's Republic of China.
Institute of Neuroscience, Soochow University, Suzhou, 215123, People's Republic of China.
Cell Commun Signal. 2022 May 28;20(1):74. doi: 10.1186/s12964-022-00894-4.
Depression is one of the most common psychiatric diseases. The monoamine transmitter theory suggests that neurotransmitters are involved in the mechanism of depression; however, the regulation on serotonin production is still unclear. We previously showed that Ahi1 knockout (KO) mice exhibited depression-like behavior accompanied by a significant decrease in brain serotonin.
In the present study, western blot, gene knockdown, immunofluorescence, dual-luciferase reporter assay, and rescue assay were used to detect changes in the Ahi1/GR/ERβ/TPH2 pathway in the brains of male stressed mice and male Ahi1 KO mice to explain the pathogenesis of depression-like behaviors. In addition, E2 levels in the blood and brain of male and female mice were measured to investigate the effect on the ERβ/TPH2 pathway and to reveal the mechanisms for the phenomenon of gender differences in depression-like behaviors.
We found that the serotonin-producing pathway-the ERβ/TPH2 pathway was inhibited in male stressed mice and male Ahi1 KO mice. We further demonstrated that glucocorticoid receptor (GR) as a transcription factor bound to the promoter of ERβ that contains glucocorticoid response elements and inhibited the transcription of ERβ. Our recent study had indicated that Ahi1 regulates the nuclear translocation of GR upon stress, thus proposing the Ahi1/GR/ERβ/TPH2 pathway for serotonin production. Interestingly, female Ahi1 KO mice did not exhibit depressive behaviors, indicating sexual differences in depressive behaviors compared with male mice. Furthermore, we found that serum 17β-estradiol (E2) level was not changed in male and female mice; however, brain E2 level significantly decreased in male but not female Ahi1 KO mice. Further, ERβ agonist LY-500307 increased TPH2 expression and 5-HT production. Therefore, both Ahi1 and E2 regulate the ERβ/TPH2 pathway and involve sexual differences in brain serotonin production and depressive behaviors.
In conclusion, although it is unclear how Ahi1 controls E2 secretion in the brain, our findings demonstrate that Ahi1 regulates serotonin production by the GR/ERβ/TPH2 pathway in the brain and possibly involves the regulation on sex differences in depressive behaviors. Video Abstract.
抑郁症是最常见的精神疾病之一。单胺递质理论表明神经递质参与了抑郁症的发病机制；然而，关于血清素产生的调节仍不清楚。我们之前的研究表明，Ahi1 敲除（KO）小鼠表现出抑郁样行为，同时大脑中血清素显著减少。
在本研究中，使用 Western blot、基因敲低、免疫荧光、双荧光素酶报告基因检测和挽救实验，检测雄性应激小鼠和雄性 Ahi1 KO 小鼠大脑中 Ahi1/GR/ERβ/TPH2 通路的变化，以解释抑郁样行为的发病机制。此外，测量雄性和雌性小鼠血液和大脑中的 E2 水平，以研究对 ERβ/TPH2 通路的影响，并揭示抑郁样行为中性别差异的机制。
我们发现，产生血清素的途径——ERβ/TPH2 途径在雄性应激小鼠和雄性 Ahi1 KO 小鼠中受到抑制。我们进一步证明，糖皮质激素受体（GR）作为一种转录因子，与包含糖皮质激素反应元件的 ERβ 启动子结合，抑制 ERβ 的转录。我们最近的研究表明，Ahi1 在应激时调节 GR 的核转位，从而提出了 Ahi1/GR/ERβ/TPH2 途径来产生血清素。有趣的是，雌性 Ahi1 KO 小鼠没有表现出抑郁行为，表明与雄性小鼠相比，雌性小鼠的抑郁行为存在性别差异。此外，我们发现雄性和雌性小鼠的血清 17β-雌二醇（E2）水平没有变化；然而，在雄性而非雌性 Ahi1 KO 小鼠中，大脑 E2 水平显著降低。此外，ERβ 激动剂 LY-500307 增加了 TPH2 的表达和 5-HT 的产生。因此，Ahi1 和 E2 都调节 ERβ/TPH2 途径，并参与大脑中血清素产生和抑郁行为的性别差异。
总之，虽然 Ahi1 如何控制大脑中的 E2 分泌尚不清楚，但我们的研究结果表明，Ahi1 通过大脑中的 GR/ERβ/TPH2 途径调节血清素的产生，可能涉及对抑郁行为中性别差异的调节。
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