Copper Modulates Adult Neurogenesis in Brain Subventricular Zone.
Copper Modulates Adult Neurogenesis in Brain Subventricular Zone.
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铜对成年脑室下区神经发生的调节作用
DOI：
10.3390/ijms23179888
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发表时间：
2022-08-31
影响因子：
5.6
通讯作者：
Zheng, Wei
中科院分区：
文献类型：
--
作者：
Liu, Luke L.;van Rijn, Richard M.;Zheng, Wei
关键词：
侧脑室室管膜下区（SVZ）是成人脑内最大的高铜神经源性区域。本研究的目的是确定铜在成人神经发生中的作用，螯合不稳定的铜离子使用一个公认的铜螯合剂D-青霉胺（D-Pen）。建立了源自成年小鼠SVZ组织的神经球模型，并表征了其关于神经干/祖细胞（NSPCs）的功能。在培养的神经球中应用D-Pen可显著降低细胞内Cu水平，并逆转Cu诱导的NSPC分化和迁移抑制。随后建立了在体侧脑室（ICV）灌注模型，将D-Pen直接注入侧脑室。金属分析显示，与盐水输注对照组相比，在低剂量（0.075 μg/h）和高剂量（0.75 μ g/h）的D-Pen输注28天后，SVZ中的Cu分别选择性降低13.1%（p = 0.19）和21.4%（p < 0.05）。免疫组化研究显示，7天低剂量D-Pen输注显著增加SVZ中Ki 67（+）/Nestin（+）细胞计数28%（p < 0.05）。定量分析吻侧迁移流（RMS）和嗅球（OB）中的BrdU（+）/双皮质素（DCX）（+）新生神经母细胞进一步表明，与盐水灌注对照相比，短期低剂量D-Pen灌注导致OB中更多的新生神经母细胞，而高剂量D-Pen灌注显示OB中新生神经母细胞较少，但RMS中更多的新生神经母细胞被阻滞。长期（28天）输注显示了相似的结局。来自神经球实验的qPCR数据揭示了编码已知调节SVZ成体神经发生的关键蛋白的mRNA的表达改变，包括但不限于Shh、Dlx 2和Slit 1，以响应神经球中Cu水平的变化。进一步的免疫组化数据表明，铜螯合作用也改变了高亲和力铜摄取蛋白1（CTR 1）和金属硫蛋白3（MT3）在SVZ以及CTR 1在脉络丛，一个组织调节脑铜稳态的表达。总之，这项研究提供了第一手的证据表明，高铜水平的SVZ似乎有可能维持稳定的成人神经发生在这个神经原区。
The subventricular zone (SVZ) in lateral ventricles is the largest neurogenic region in adult brain containing high amounts of copper (Cu). This study aims to define the role of Cu in adult neurogenesis by chelating labile Cu ions using a well-established Cu chelator D-Penicillamine (D-Pen). A neurosphere model derived from adult mouse SVZ tissues was established and characterized for its functionality with regards to neural stem/progenitor cells (NSPCs). Applying D-Pen in cultured neurospheres significantly reduced intracellular Cu levels and reversed the Cu-induced suppression of NSPC’s differentiation and migration. An in vivo intracerebroventricular (ICV) infusion model was subsequently established to infuse D-Pen directly into the lateral ventricle. Metal analyses revealed a selective reduction of Cu in SVZ by 13.1% (p = 0.19) and 21.4% (p < 0.05) following D-Pen infusions at low (0.075 μg/h) and high (0.75 μg/h) doses for 28 days, respectively, compared to saline-infused controls. Immunohistochemical studies revealed that the 7-day, low-dose D-Pen infusion significantly increased Ki67(+)/Nestin(+) cell counts in SVZ by 28% (p < 0.05). Quantification of BrdU(+)/doublecortin (DCX)(+) newborn neuroblasts in the rostral migration stream (RMS) and olfactory bulb (OB) further revealed that the short-term, low-dose D-Pen infusion, as compared with saline-infused controls, resulted in more newborn neuroblasts in OB, while the high-dose D-Pen infusion showed fewer newborn neuroblasts in OB but with more arrested in the RMS. Long-term (28-day) infusion revealed similar outcomes. The qPCR data from neurosphere experiments revealed altered expressions of mRNAs encoding key proteins known to regulate SVZ adult neurogenesis, including, but not limited to, Shh, Dlx2, and Slit1, in response to the changed Cu level in neurospheres. Further immunohistochemical data indicated that Cu chelation also altered the expression of high-affinity copper uptake protein 1 (CTR1) and metallothionein-3 (MT3) in the SVZ as well as CTR1 in the choroid plexus, a tissue regulating brain Cu homeostasis. Taken together, this study provides first-hand evidence that a high Cu level in SVZ appears likely to maintain the stability of adult neurogenesis in this neurogenic zone.
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