The promotion of neurogenesis is considered to be an effective therapeutic strategy for neuropsychiatric disorders because impairment of neurogenesis is associated with the onset and progression of these disorders. We have previously demonstrated that orally ingested ergothioneine (ERGO), a naturally occurring antioxidant and hydrophilic amino acid, promotes neurogenesis in the hippocampal dentate gyrus (DG) with its abundant neural stem cells (NSCs) and exerts antidepressant-like effects in mice. Independent of its antioxidant activities, ERGO induces in cultured NSCs this differentiation through induction of the basic helix-loop-helix transcription factor Math1. However, the upstream signaling of Math1 in the mechanisms underlying ERGO-induced neuronal differentiation remains unclear. The purpose of the present study was to elucidate the upstream signaling with the aim of discovering novel targets for the treatment of neuropsychiatric disorders. We focused on neurotrophic factor signaling, as it is important for the promotion of neurogenesis and the induction of antidepressant effects. We also focused on the signaling of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a known amino acid sensor, and the members of this signaling pathway, mTOR and p70 ribosomal protein S6 kinase 1 (S6K1). Exposure of cultured NSCs to ERGO significantly increased the expression of phosphorylated S6K1 (p-S6K1) at Thr389 in only 1 h, of phosphorylated mTOR (p-mTOR) in 6 h, and of the gene product of neurotrophin 4/5 (NT5) which activates tropomyosin receptor kinase B (TrkB) in 24 h. ERGO increased the population of βIII-tubulin-positive neurons, and this effect was suppressed by the inhibitors of S6K1 (PF4708671), mTORC1 (rapamycin), and TrkB (GNF5837). Oral administration of ERGO to mice significantly increased in the DG the expression of p-S6K1 at Thr389, the gene product of NT5, and phosphorylated TrkB but not that of p-mTOR. Thus, neuronal differentiation of NSCs induced by ERGO is mediated, at least in part, through phosphorylation of S6K1 at Thr389 and subsequent activation of TrkB signaling through the induction of NT5. Thus, S6K1 and NT5 might be promising target molecules for the treatment of neuropsychiatric disorders.

中文翻译：

---

麦角硫因诱导的神经元分化通过鼠神经干细胞中S6K1和神经营养蛋白4 / 5-TrkB信号传导的激活而介导。

神经发生的促进被认为是神经精神疾病的有效治疗策略，因为神经发生的损害与这些疾病的发作和发展有关。我们以前已经证明，口服摄取的麦角硫氨酸（ERGO）是一种天然存在的抗氧化剂和亲水性氨基酸，通过其丰富的神经干细胞（NSC）促进海马齿状回（DG）的神经发生，并在小鼠中发挥抗抑郁样作用。ERGO不受其抗氧化活性的影响，通过诱导基本的螺旋-环-螺旋转录因子Math1在培养的NSC中诱导这种分化。然而，在ERGO诱导的神经元分化的潜在机制中Math1的上游信号仍然不清楚。本研究的目的是阐明上游信号，以发现用于治疗神经精神疾病的新靶标。我们专注于神经营养因子信号传导，因为它对于促进神经发生和诱导抗抑郁作用很重要。我们还着眼于雷帕霉素（mTOR）复合物1（mTORC1）的哺乳动物靶标的信号，一种已知的氨基酸传感器，以及该信号通路的成员mTOR和p70核糖体蛋白S6激酶1（S6K1）。仅在1小时内，将培养的NSC暴露于ERGO即可显着提高Thr389磷酸化S6K1（p-S6K1）的表达，在6小时内磷酸化mTOR（p-mTOR）的表达以及神经营养蛋白4/5（NT5）的基因产物在24小时内激活原肌球蛋白受体激酶B（TrkB）。ERGO增加了βIII-微管蛋白阳性神经元的数量，这种作用被S6K1（PF4708671），mTORC1（雷帕霉素）和TrkB（GNF5837）的抑制剂所抑制。对小鼠口服ERGO可使DG中p-S6K1在Thr389（NT5的基因产物）和磷酸化的TrkB磷酸化，但p-mTOR的磷酸化却没有明显增加。因此，由ERGO诱导的NSC的神经元分化至少部分地通过在Thr389处S6K1的磷酸化和随后通过NT5的诱导而激活TrkB信号传导来介导。因此，S6K1和NT5可能是治疗神经精神疾病的有希望的靶分子。对小鼠口服ERGO可使DG中p-S6K1在Thr389（NT5的基因产物）和磷酸化的TrkB磷酸化，但p-mTOR的磷酸化却没有明显增加。因此，由ERGO诱导的NSC的神经元分化至少部分地通过在Thr389处S6K1的磷酸化和随后通过NT5的诱导而激活TrkB信号传导来介导。因此，S6K1和NT5可能是治疗神经精神疾病的有希望的靶分子。对小鼠口服ERGO可使DG中p-S6K1在Thr389（NT5的基因产物）和磷酸化的TrkB磷酸化，但p-mTOR的磷酸化却没有明显增加。因此，由ERGO诱导的NSC的神经元分化至少部分地通过在Thr389处S6K1的磷酸化和随后通过NT5的诱导而激活TrkB信号传导来介导。因此，S6K1和NT5可能是治疗神经精神疾病的有希望的靶分子。