Cortical spreading depolarization waves, the cause underlying migraine aura, are also the markers and mechanism of pathology in the acutely injured human brain. Propagation of spreading depolarization wave uniquely depends on the interaction between presynaptic and postsynaptic glutamate N-methyl-d-aspartate receptors (NMDARs). In the normally perfused brain, even a single wave causes a massive depolarization of neurons and glia, which results in transient loss of neuronal function and depression of the ongoing electrocorticographic activity. Endoplasmic reticulum is the cellular organelle of particular importance for modulation of neurotransmission. Neuronal endoplasmic reticulum structure is assumed to be persistently continuous in neurons, but is rapidly lost within 1 to 2 min of global cerebral ischaemia, i.e. the organelle disintegrates by fission. This phenomenon appears to be timed with the cardiac arrest-induced cortical spreading depolarizations, rather than ensuing cell death. To what extent NMDAR-dependent processes may trigger neuronal endoplasmic reticulum fission and whether fission is reversible in the normally perfused brain is unknown. We used two-photon microscopy to examine neuronal endoplasmic reticulum structural dynamics during whisker stimulation and cortical spreading depolarizations in vivo. Somatosensory stimulation triggered loss of endoplasmic reticulum continuity, a likely outcome of constriction and fission, in dendritic spines within less than 10 s of stimulation, which was spontaneously reversible and recovery to normal took 5 min. The endoplasmic reticulum fission was inhibited by blockade of NMDAR and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) activated downstream of the NMDARs, whereas inhibition of guanosine triphosphate hydrolases hindered regain of endoplasmic reticulum continuity, i.e. fusion. In contrast to somatosensory stimulation, endoplasmic reticulum fission during spreading depolarization was widespread and present in dendrites and spines, and was preceded by dramatic rise in intracellular Ca²⁺. The endoplasmic reticulum fission during spreading depolarization was more persistent, as 1 h after the depolarization cortical neurons still exhibited loss of endoplasmic reticulum continuity. Notably, endoplasmic reticulum fission was accompanied with loss of electrocorticographic activity, whereas subsequent regain of synaptic function paralleled the organelle fusion. Furthermore, blocking CaMKII activity partly rescued endoplasmic reticulum fission and markedly shortened the recovery time of brain spontaneous activity. Thus, prevention of endoplasmic reticulum fission with CaMKII inhibitors may be a novel strategy to rescue brain function in patients with migraine and a promising therapeutic avenue in the acutely injured brain.

中文翻译：

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CaMKII依赖性内质网裂变的晶须刺激和皮层扩散去极化过程中。

皮层传播的去极化波，是偏头痛先兆的根本原因，也是急性受伤的人脑中病理学的标志和机制。扩展去极化波的传播唯一取决于突触前和突触后谷氨酸N-甲基-d之间的相互作用-天冬氨酸受体（NMDARs）。在正常灌注的大脑中，即使是单个波，也会引起神经元和神经胶质的大量去极化，从而导致神经元功能的暂时丧失和正在进行的脑皮层活动的降低。内质网是调节神经传递特别重要的细胞器。假定神经元内质网结构在神经元中是连续连续的，但在全脑缺血后的1至2分钟内迅速丧失，即细胞器因裂变而分解。这种现象似乎与心脏骤停引起的皮质扩散性去极化的时机有关，而不是伴随细胞死亡。NMDAR依赖性过程可能在多大程度上触发神经内质网裂变，以及在正常灌注的大脑中裂变是否可逆尚不清楚。我们使用双光子显微镜检查晶须刺激和皮层扩展去极化过程中神经元内质网的结构动力学体内。体感刺激在不到10 s的刺激内触发了树突棘的内质网连续性丧失，这可能是收缩和裂变的结果，该过程可自发逆转，恢复正常需要5分钟。内质网裂变被NMDAR的阻断和CaDAR依赖的Ca ²⁺ /钙调蛋白依赖性蛋白激酶II（CaMKII）激活所抑制，而鸟嘌呤三磷酸鸟苷水解酶的抑制则阻碍了内质网连续性的恢复，即融合。与体感刺激相反，扩散去极化过程中的内质网裂变普遍存在并存在于树突和棘中，并且在此之前细胞内Ca ²⁺急剧增加。。在去极化过程中，内质网裂变更为持久，因为去极化后1小时皮质神经元仍表现出内质网连续性的丧失。值得注意的是，内质网裂变伴随着皮层电活动的丧失，而随后突触功能的恢复与细胞器融合平行。此外，阻断CaMKII活性可部分挽救内质网裂变，并显着缩短脑自发性活动的恢复时间。因此，用CaMKII抑制剂预防内质网裂变可能是挽救偏头痛患者脑功能的新策略，也是急性受伤脑部的有希望的治疗途径。