Sustained NMDA receptor activation by spreading depolarizations can initiate excitotoxic injury in metabolically compromised neurons
Sustained NMDA receptor activation by spreading depolarizations can initiate excitotoxic injury in metabolically compromised neurons
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DOI：
10.1113/jphysiol.2012.234476
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发表时间：
2012-11-01
影响因子：
5.5
通讯作者：
Shuttleworth, C. William
中科院分区：
文献类型：
--
作者：
Aiba, Isamu;Shuttleworth, C. William
扩展去极化（SD）是缓慢传播的几乎完全的神经元和神经胶质细胞去极化波。脑损伤患者中已记录SD，SD的发生率与结局严重程度显著相关。虽然它是公认的，SD的离子动态平衡障碍提出了一个严重的代谢负担，目前有有限的了解SD诱导的损伤过程在细胞水平。在目前的研究中，我们的特点是伴随SD的事件在海马CA1区的小鼠脑切片，使用全细胞记录和单细胞钙离子成像。我们确定了一个兴奋阶段，持续约2分钟后SD发病，并伴有延迟树突状离子动态平衡障碍。兴奋相一致的突触前谷氨酸释放的显着增加，证明了自发EPSC频率和成对脉冲抑郁症诱发EPSC的短暂增加。NMDA受体（NMDARs）的激活，在此晚兴奋相的持续时间的个别神经元去极化和延迟恢复的细胞外慢电位的变化。SD发作后选择性靶向NMDAR激活（通过延迟压力应用竞争性NMDAR拮抗剂）显著降低了细胞去极化的持续时间。SD后树突状细胞Ca2+升高的恢复也对延迟NMDA拮抗剂的应用敏感。神经元能量代谢的部分抑制将SD转化为不可恢复的事件，伴有持续的Ca 2+过载和膜损伤。延迟NMDAR阻断足以防止代谢受损神经元中的这些急性损伤事件。这些结果确定了一个显着的贡献，可能是神经元损伤的病理情况下，SD的晚期成分。
Spreading depolarizations (SDs) are slowly propagating waves of near-complete neuronal and glial depolarization. SDs have been recorded in patients with brain injury, and the incidence of SD significantly correlates with outcome severity. Although it is well accepted that the ionic dyshomeostasis of SD presents a severe metabolic burden, there is currently limited understanding of SD-induced injury processes at a cellular level. In the current study we characterized events accompanying SD in the hippocampal CA1 region of murine brain slices, using whole-cell recordings and single-cell Ca2+ imaging. We identified an excitatory phase that persisted for approximately 2 min following SD onset, and accompanied with delayed dendritic ionic dyshomeostasis. The excitatory phase coincided with a significant increase in presynaptic glutamate release, evidenced by a transient increase in spontaneous EPSC frequency and paired-pulse depression of evoked EPSCs. Activation of NMDA receptors (NMDARs) during this late excitatory phase contributed to the duration of individual neuronal depolarizations and delayed recovery of extracellular slow potential changes. Selectively targeting the NMDAR activation following SD onset (by delayed pressure application of a competitive NMDAR antagonist) significantly decreased the duration of cellular depolarizations. Recovery of dendritic Ca2+ elevations following SD were also sensitive to delayed NMDA antagonist application. Partial inhibition of neuronal energy metabolism converted SD into an irrecoverable event with persistent Ca2+ overload and membrane compromise. Delayed NMDAR block was sufficient to prevent these acute injurious events in metabolically compromised neurons. These results identify a significant contribution of a late component of SD that could underlie neuronal injury in pathological circumstances.