Fontaine Romain H, Olivier Paul, Massonneau Véronique, Leroux Philippe, Degos Vincent, Lebon Sophie, El Ghouzzi Vincent, Lelièvre Vincent, Gressens Pierre, Baud Olivier
Institut National de la Santé et de la Recherche Médicale, AVENIR RO5230HS, Paris, France.
Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16779-84. doi: 10.1073/pnas.0803004105. Epub 2008 Oct 15.
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 immunocytochemistry, 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. Intracerebral 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.
白质损伤是导致神经功能障碍的主要原因。尽管缺氧缺血和兴奋性毒性是主要的致病因素，但最近有研究表明遗传因素也发挥了作用。因此，长期的孕期缺氧与新生大鼠的白质损伤（WMD）有关，但与新生小鼠无关。实际上，在出生后第1天（P1）和第10天（P10），小鼠和大鼠幼崽的小胶质细胞活化和血管壁密度均增加，但只有缺氧的大鼠幼崽出现了细胞死亡、星形胶质细胞增生和髓鞘形成的显著改变。我们通过免疫细胞化学、聚合酶链反应（PCR）和兴奋性毒性双重打击损伤实验，研究了这种物种相关差异是否归因于产前缺氧对谷氨酸受体亚基表达的影响。对P1期缺氧小鼠幼崽进行定量PCR分析，结果显示α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体亚基-1、-2和-4、海人藻酸受体亚基谷氨酸受体7（GluR7）以及代谢型谷氨酸受体亚基mGluR1、-2、-3、-5和-7的表达下调了2至4倍。缺氧大鼠幼崽的谷氨酸受体亚基均未下调。NR2B是唯一在P1期缺氧小鼠而非缺氧大鼠中表达下调的N-甲基-D-天冬氨酸（NMDA）受体亚基。给予艾芬地尔以诱导含NR2B亚基的NMDA受体功能抑制，可预防缺氧大鼠幼崽的髓鞘形成延迟。脑内注射谷氨酸激动剂后，缺氧小鼠幼崽中鹅膏蕈氨酸诱导的兴奋性毒性损伤比正常小鼠幼崽的损伤减少得更多。孕期缺氧可能会调节胎鼠而非胎鼠体内特定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白质损伤的易感性。
