Zinc transporter 3 modulates cell proliferation and neuronal differentiation in the adult hippocampus
Zinc transporter 3 modulates cell proliferation and neuronal differentiation in the adult hippocampus
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DOI：
10.1002/stem.3194
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发表时间：
2020-05-07
期刊：
影响因子：
5.2
通讯作者：
Suh, Sang Won
中科院分区：
文献类型：
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作者：
Choi, Bo Young;Hong, Dae Ki;Suh, Sang Won
齿状回的颗粒下区是海马体的一个子区域，具有两个独特的特征：它是成人神经发生最活跃的部位之一，也是突触锌浓度最高的位置，即苔藓纤维末端。因此，我们试图研究囊泡锌作为海马成人神经发生调节剂的作用。在这里，我们使用突触小泡锌耗尽的 ZnT3(-/-) 小鼠来测试靶向删除该转运蛋白对成体神经发生的影响。我们发现这种操作减少了祖细胞更新，并导致在 DG 中存活的新生细胞向神经元表型的成熟过程中出现明显缺陷。我们还研究了锌 (ZnCl2)、n-乙酰半胱氨酸 (NAC) 和 ZnCl2 加 2NAC (ZN) 补充剂对成人海马神经发生的影响。与 ZnCl2 或 NAC 相比，施用 ZN 导致祖细胞和神经母细胞增殖增加。 ZN 还通过提高胰岛素样生长因子-1 和 ERK/CREB 激活来挽救 ZnT3 缺失相关的神经发生减少。总之，这些发现表明，ZnT3 在维持成年海马神经发生中发挥着非常重要的作用，补充 ZN 对海马神经发生具有有益作用，并为增强损伤后的神经保护和修复提供治疗靶点，这一点通过其预防 ZnT3(-/-) 小鼠衰老依赖性认知衰退的能力得到证明。因此，本研究表明 ZnT3 和囊泡锌对于成人海马神经发生至关重要。
The subgranular zone of the dentate gyrus is a subregion of the hippocampus that has two uniquely defining features; it is one of the most active sites of adult neurogenesis as well as the location where the highest concentrations of synaptic zinc found, the mossy fiber terminals. Therefore, we sought to investigate the idea that vesicular zinc plays a role as a modulator of hippocampal adult neurogenesis. Here, we used ZnT3( -/-) mice, which are depleted of synaptic-vesicle zinc, to test the effect of targeted deletion of this transporter on adult neurogenesis. We found that this manipulation reduced progenitor cell turnover as well as leading to a marked defect in the maturation of newborn cells that survive in the DG toward a neuronal phenotype. We also investigated the effects of zinc (ZnCl2), n-acetyl cysteine (NAC), and ZnCl2 plus 2NAC (ZN) supplement on adult hippocampal neurogenesis. Compared with ZnCl2 or NAC, administration of ZN resulted in an increase in proliferation of progenitor cells and neuroblast. ZN also rescued the ZnT3 loss-associated reduction of neurogenesis via elevation of insulin-like growth factor-1 and ERK/CREB activation. Together, these findings reveal that ZnT3 plays a highly important role in maintaining adult hippocampal neurogenesis and supplementation by ZN has a beneficial effect on hippocampal neurogenesis, as well as providing a therapeutic target for enhanced neuroprotection and repair after injury as demonstrated by its ability to prevent aging-dependent cognitive decline in ZnT3( -/-) mice. Therefore, the present study suggests that ZnT3 and vesicular zinc are essential for adult hippocampal neurogenesis.