A neuroprotective role of the NMDA receptor subunit GluN3A (NR3A) in ischemic stroke of the adult mouse.
A neuroprotective role of the NMDA receptor subunit GluN3A (NR3A) in ischemic stroke of the adult mouse.
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DOI：
10.1152/ajpcell.00353.2014
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发表时间：
2015-04
期刊：
影响因子：
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通讯作者：
J. Lee;Zheng Zachory Wei;Dongdong Chen;Xiaohuan Gu;Ling Wei;S. Yu
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文献类型：
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作者：
J. Lee;Zheng Zachory Wei;Dongdong Chen;Xiaohuan Gu;Ling Wei;S. Yu
GluN3A或NR3A是发育调控的n -甲基-d-天冬氨酸受体（NMDAR）亚基，具有独特的抑制作用，可降低NMDAR电流和受体介导的Ca（2+）内流。在新生儿大脑中，GluN3A被证明与突触成熟和脊柱形成有关，并发挥神经保护作用。然而，它在成人大脑中的功能作用在很大程度上是未知的。我们验证了这样的假设，即不考虑GluN3A在成人大脑中相对较低的表达水平，这种抑制性NMDAR亚基对缺血诱导的脑损伤具有保护作用。在野生型（WT）和GluN3A基因敲除（KO）小鼠中，通过永久性阻断大脑中动脉（MCA）右远端分支并结扎10分钟的双颈总动脉（CCAs）来诱导局灶性脑缺血。局灶性脑缺血24小时后，GluN3A KO小鼠与WT小鼠相比，用2,3,5-三苯基氯化四唑（TTC）染色评估的梗死体积明显更大。末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）染色显示GluN3A KO小鼠细胞死亡增强。此外，GluN3A的缺失阻碍了卒中后感觉运动功能的恢复。提示，尽管GluN3A在成人脑中的表达水平相对较低，但在缺血诱导的兴奋毒性和脑损伤中仍是一个值得关注的调节因子。
GluN3A or NR3A is a developmentally regulated N-methyl-d-aspartate receptor (NMDAR) subunit, showing a unique inhibitory role that decreases NMDAR current and the receptor-mediated Ca(2+) influx. In the neonatal brain, GluN3A is shown to associate with synaptic maturation and spine formation and plays a neuroprotective role. Its functional role in the adult brain, however, is largely unknown. We tested the hypothesis that, disrespecting the relatively lower expression level of GluN3A in the adult brain, this inhibitory NMDAR subunit shows a protective action against ischemia-induced brain injury. In littermate wild-type (WT) and GluN3A knockout (KO) mice, focal cerebral ischemia was induced by permanent occlusion of right distal branches of the middle cerebral artery (MCA) plus 10-min ligation of both common carotid arteries (CCAs). Twenty-four hours after focal cerebral ischemia, the infarction volume assessed using 2,3,5-triphenyltetrazolium chloride (TTC) staining was significantly larger in GluN3A KO mice compared with WT mice. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining demonstrated enhanced cell death in GluN3A KO mice. Moreover, the deletion of GluN3A hindered sensorimotor functional recovery after stroke. It is suggested that, although the expression level is relatively lower in the adult brain, GluN3A is still a noteworthy regulator in ischemia-induced excitotoxicity and brain injury.