Developmental Expression of N-Methyl-D-Aspartate (NMDA) Receptor Subunits in Human White and Gray Matter: Potential Mechanism of Increased Vulnerability in the Immature Brain
Developmental Expression of N-Methyl-D-Aspartate (NMDA) Receptor Subunits in Human White and Gray Matter: Potential Mechanism of Increased Vulnerability in the Immature Brain
复制标题
DOI：
10.1093/cercor/bht246
复制
发表时间：
2015-02-01
期刊：
影响因子：
3.7
通讯作者：
Jensen, Frances E.
中科院分区：
文献类型：
--
作者：
Jantzie, Lauren L.;Talos, Delia M.;Jensen, Frances E.
围产期脑损伤的病理生理学是多因素的，涉及缺氧缺血（HI）和炎症。N-甲基-D-天冬氨酸受体（NMDAR）存在于未成熟啮齿动物的神经元和神经胶质细胞上，NMDAR拮抗剂在HI模型中具有保护作用。为了提高啮齿类动物数据的临床翻译，我们研究了6个NMDAR亚基的蛋白表达在死后人类大脑没有损伤，从20周的产后到成年期，并在脑室周围白质软化症（PVL）的情况下。我们假设发育中的大脑本质上容易受到兴奋性毒性通过成熟特异性NMDAR水平和亚基组成。在正常的白色物质中，NR 1和NR 2B水平在早产期比成年期高。在灰质中，NR 2A和NR 3A的表达近期最高。与未受伤的对照组相比，PVL白色物质中NR 2A显著升高，灰质中NR 1和NR 3A降低。这些数据表明，由于个体受体亚基的整体上调，在早期脑发育过程中NMDAR介导的脆弱性增加，特别是存在高钙渗透性的含NR 2B和镁不敏感的NR 3A NMDAR。这些数据提高了对人脑发育中NMDAR亚基表达的分子多样性和异质性的理解，并支持谷氨酸介导的损伤的内在产前脆弱性;验证了PVL的NMDAR亚基特异性靶向治疗。
The pathophysiology of perinatal brain injury is multifactorial and involves hypoxia-ischemia (HI) and inflammation. N-methyl-D-aspartate receptors (NMDAR) are present on neurons and glia in immature rodents, and NMDAR antagonists are protective in HI models. To enhance clinical translation of rodent data, we examined protein expression of 6 NMDAR subunits in postmortem human brains without injury from 20 postconceptional weeks through adulthood and in cases of periventricular leukomalacia (PVL). We hypothesized that the developing brain is intrinsically vulnerable to excitotoxicity via maturation-specific NMDAR levels and subunit composition. In normal white matter, NR1 and NR2B levels were highest in the preterm period compared with adult. In gray matter, NR2A and NR3A expression were highest near term. NR2A was significantly elevated in PVL white matter, with reduced NR1 and NR3A in gray matter compared with uninjured controls. These data suggest increased NMDAR-mediated vulnerability during early brain development due to an overall upregulation of individual receptors subunits, in particular, the presence of highly calcium permeable NR2B-containing and magnesium-insensitive NR3A NMDARs. These data improve understanding of molecular diversity and heterogeneity of NMDAR subunit expression in human brain development and supports an intrinsic prenatal vulnerability to glutamate-mediated injury; validating NMDAR subunit-specific targeted therapies for PVL.