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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Vulnerability Of White Matter Towards Antenatal Hypoxia Is Linked To A Species-dependent Regulation Of Glutamate Receptor Subunits
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Vulnerability Of White Matter Towards Antenatal Hypoxia Is Linked To A Species-dependent Regulation Of Glutamate Receptor Subunits

机译：朝向产前缺氧的白色物质的脆弱性与谷氨酸受体亚单位的物种依赖性调节有关。

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摘要

White-matter damage is a leading cause of neurological handicap. Although hypoxia-ischemia and excitotoxicity are major pathogenic factors, a role for genetic influences was suggested recently. Thus, protracted gestational hypoxia was associated with white-matter damage (WMD) in rat pups but not in mouse pups. Indeed, microglial activation and vessel-wall density on postnatal days (P)1 and P10 were found increased in both mouse and rat pups, but cell death, astrogliosis, and myelination were only significantly altered in hypoxic rat pups. We investigated whether this species-related difference was ascribable to effects of antenatal hypoxia on the expression of glutamate receptor subunits by using immunocyto-chemistry, PCR, and excitotoxic double hit insult. Quantitative PCR in hypoxic mouse pups on P1 showed 2- to 4-fold down-regulation of the AMPA-receptor subunits -1,2, and -4; of the kainate-receptor subunit GluR7; and of the metabotropic receptor subunits mGluR1, -2, -3, -5, and -7. None of the glutamate-receptor subunits was down-regulated in the hypoxic rat pups. NR2B was the only NMDA-receptor subunit that was down-regulated in hypoxic mice but not in hypoxic rat on P1. Ifenprodil administration to induce functional inhibition of NMDA containing NR2B-subunit receptors prevented hypoxia-induced myelination delay in rat pups. Intra-cerebral injection of a glutamate agonist produced a larger decrease in ibotenate-induced excitotoxic lesions in hypoxic mouse pups than in normoxic mouse pups. Gestational hypoxia may regulate the expression of specific glutamate-receptor subunits in fetal mice but not in fetal rats. Therefore, genetic factors may influence the susceptibility of rodents to WMD.
机译：白质损伤是神经障碍的主要原因。尽管缺氧缺血和兴奋性毒性是主要的致病因素，但最近有人提出了遗传影响的作用。因此，长期妊娠缺氧与小白鼠的白质损害（WMD）有关，而与小白鼠无关。的确，在小鼠和大鼠幼崽中发现出生后第（P）1和P10天的小胶质细胞活化和血管壁密度增加，但是低氧大鼠幼崽的细胞死亡，星形胶质细胞增多症和髓鞘化只有明显改变。我们通过使用免疫细胞化学，PCR和兴奋性毒性双重打击来研究这种与物种相关的差异是否归因于产前低氧对谷氨酸受体亚基表达的影响。低氧小鼠幼崽在P1上的定量PCR显示AMPA受体亚基-1,2和-4的下调2至4倍；海藻酸盐受体亚基GluR7的序列；和代谢型受体亚基mGluR1，-2，-3，-5和-7。缺氧大鼠幼崽中的谷氨酸受体亚基均未下调。 NR2B是在缺氧小鼠中唯一被下调的NMDA受体亚基，但在P1的缺氧大鼠中不是。 Ifenprodil的给药可诱导含有NR2B亚基受体的NMDA的功能性抑制，从而可防止低氧诱导的大鼠幼崽的髓鞘延迟。大脑内注射谷氨酸激动剂与低氧小鼠相比，在低氧小鼠幼鼠中由ibotenate诱导的兴奋毒性损伤的减少更大。妊娠缺氧可能调节胎鼠中特定谷氨酸受体亚基的表达，但不能调节胎鼠中的谷氨酸受体亚基的表达。因此，遗传因素可能会影响啮齿动物对WMD的敏感性。

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