Region-specific role for GluN2B-containing NMDA receptors in injury to Purkinje cells and CA1 neurons following global cerebral ischemia.
Region-specific role for GluN2B-containing NMDA receptors in injury to Purkinje cells and CA1 neurons following global cerebral ischemia.
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DOI：
10.1016/j.neuroscience.2014.10.033
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发表时间：
2015-01-22
期刊：
影响因子：
3.3
通讯作者：
Herson, P. S.
中科院分区：
文献类型：
--
作者：
Quillinan, N.;Grewal, H.;Deng, G.;Shimizu, K.;Yonchek, J. C.;Strnad, F.;Traystman, R. J.;Herson, P. S.
心脏骤停幸存者存在运动缺陷，小脑浦肯野细胞(PC)的损伤可能导致运动协调性受损和缺氧后的肌阵挛。NMDA受体介导的兴奋性毒性是几个脑区细胞死亡的一种公认的机制，但NMDA受体在PC损伤中的作用尚不清楚。在大脑皮层和海马神经元中出现的数据表明，含有GluN2A的NMDA受体发出信号以改善细胞存活，而含有GluN2B的受体有助于神经元损伤。本研究采用小鼠心脏骤停心肺复苏(CA/CPR)模型，比较了PC和CA1区神经元损伤情况，并探讨了NMDA受体在PC损伤中的作用。细胞密度分析显示，CA/CPR后24小时内PC丢失24%，7天后细胞损伤稳定在33%。亚单位混杂NMDA受体拮抗剂MK-801对CA/CPR后CA1神经元和PC细胞的缺血损伤具有保护作用，表明NMDA受体激活在这两个脑区的损伤中起作用。相反，GluN2B拮抗剂Co 101244对浦肯野细胞的损失没有影响，但对CA1区的损伤有保护作用。这些数据表明，与海马CA1区神经元相比，小脑PC的缺血性损伤是通过不同的细胞死亡机制进行的。
Motor deficits are present in cardiac arrest survivors and injury to cerebellar Purkinje cells (PCs) likely contribute to impairments in motor coordination and post-hypoxic myoclonus. NMDA receptor mediated excitotoxicity is a well-established mechanism of cell death in several brain regions, but the role of NMDA receptors in PC injury remains understudied. Emerging data in cortical and hippocampal neurons indicates that the GluN2A-containing NMDA receptors signal to improve cell survival and GluN2B-containing receptors contribute to neuronal injury. This study compared neuronal injury in the hippocampal CA1 region to that in PCs and investigated the role of NMDA receptors in PC injury in our mouse model of cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Analysis of cell density demonstrated a 24% loss of PCs within 24 hours after 8 min CA/CPR and injury stabilized to 33% by 7 days. The subunit promiscuous NMDA receptor antagonist MK-801 protected both CA1 neurons and PCs from ischemic injury following CA/CPR, demonstrating a role for NMDA receptor activation in injury to both brain regions. In contrast, the GluN2B antagonist, Co 101244, had no effect on Purkinje cell loss while protecting against injury in the CA1 region. These data indicate that ischemic injury to cerebellar PCs progresses via different cell death mechanisms compared to hippocampal CA1 neurons.
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