Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey.
Department of Neurosurgery, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
J Headache Pain. 2022 Aug 19;23(1):107. doi: 10.1186/s10194-022-01474-0.
Unlike the spontaneously appearing aura in migraineurs, experimentally, cortical spreading depression (CSD), the neurophysiological correlate of aura is induced by non-physiological stimuli. Consequently, neural mechanisms involved in spontaneous CSD generation, which may provide insight into how migraine starts in an otherwise healthy brain, remain largely unclear. We hypothesized that CSD can be physiologically induced by sensory stimulation in primed mouse brain.
Cortex was made susceptible to CSD with partial inhibition of Na/K-ATPase by epidural application of a low concentration of Na/K-ATPase blocker ouabain, allowing longer than 30-min intervals between CSDs or by knocking-down α2 subunit of Na/K-ATPase, which is crucial for K and glutamate re-uptake, with shRNA. Stimulation-triggered CSDs and extracellular K changes were monitored in vivo electrophysiologically and a K-sensitive fluoroprobe (IPG-4), respectively.
After priming with ouabain, photic stimulation significantly increased the CSD incidence compared with non-stimulated animals (44.0 vs. 4.9%, p < 0.001). Whisker stimulation also significantly increased the CSD incidence, albeit less effectively (14.9 vs. 2.4%, p = 0.02). Knocking-down Na/K-ATPase (50% decrease in mRNA) lowered the CSD threshold in all mice tested with KCl but triggered CSDs in 14.3% and 16.7% of mice with photic and whisker stimulation, respectively. Confirming Na/K-ATPase hypofunction, extracellular K significantly rose during sensory stimulation after ouabain or shRNA treatment unlike controls. In line with the higher CSD susceptibility observed, K rise was more prominent after ouabain. To gain insight to preventive mechanisms reducing the probability of stimulus-evoked CSDs, we applied an A1-receptor antagonist (DPCPX) to the occipital cortex, because adenosine formed during stimulation from ATP can reduce CSD susceptibility. DPCPX induced spontaneous CSDs but only small-DC shifts along with suppression of EEG spikes during photic stimulation, suggesting that the inhibition co-activated with sensory stimulation could limit CSD ignition when K uptake was not sufficiently suppressed as with ouabain.
Normal brain is well protected against CSD generation. For CSD to be ignited under physiological conditions, priming and predisposing factors are required as seen in migraine patients. Intense sensory stimulation has potential to trigger CSD when co-existing conditions bring extracellular K and glutamate concentrations over CSD-ignition threshold and stimulation-evoked inhibitory mechanisms are overcome.
与偏头痛患者自发出现的先兆不同，皮质扩散性抑制（CSD）是一种神经生理学相关现象，可通过非生理刺激诱发。因此，与自发性 CSD 产生相关的神经机制仍不清楚，而这种机制可能有助于了解偏头痛如何在健康的大脑中发作。我们假设，通过对预先处理的小鼠大脑施加低浓度的 Na/K-ATP 酶抑制剂哇巴因，可使皮质对 CSD 敏感，从而在生理上诱导 CSD，因为该处理方法可部分抑制 Na/K-ATP 酶，从而使 CSD 之间的间隔超过 30 分钟，或者通过短发夹 RNA（shRNA）敲低 Na/K-ATP 酶的α2 亚基，该亚基对于 K 和谷氨酸的再摄取至关重要。通过在体电生理学和 K 敏感荧光探针（IPG-4）分别监测刺激触发的 CSD 和细胞外 K 的变化。
在用哇巴因预处理后，与未受刺激的动物相比，光刺激显著增加了 CSD 的发生率（44.0%比 4.9%，p<0.001）。触须刺激也显著增加了 CSD 的发生率，尽管效果不如光刺激（14.9%比 2.4%，p=0.02）。敲低 Na/K-ATP 酶（mRNA 降低 50%）使所有接受 KCl 测试的小鼠的 CSD 阈值降低，但在光刺激和触须刺激下，分别有 14.3%和 16.7%的小鼠发生 CSD。与对照组相比，在用哇巴因或 shRNA 处理后，由于刺激过程中形成的三磷酸腺苷可降低 CSD 的敏感性，因此，细胞外 K 在感觉刺激期间明显升高。与观察到的更高的 CSD 易感性一致，哇巴因处理后 K 升高更为显著。为了深入了解降低刺激诱发 CSD 概率的预防机制，我们将 A1 受体拮抗剂（DPCPX）应用于枕叶皮层，因为在 ATP 刺激期间形成的腺苷可以降低 CSD 的敏感性。DPCPX 诱导自发性 CSD，但在光刺激期间仅伴随着小的 DC 偏移和 EEG 尖峰抑制，这表明当 K 摄取没有被哇巴因充分抑制时，与感觉刺激共同激活的抑制作用可能会限制 CSD 的点火。
正常大脑对 CSD 的产生有很好的保护作用。在偏头痛患者中可见到，CSD 要在生理条件下被引发，需要有引发和促成因素。当共存条件使细胞外 K 和谷氨酸浓度超过 CSD 点火阈值，并克服刺激引发的抑制机制时，强烈的感觉刺激可能会引发 CSD。
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