Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey.
Current address for Dr Gursoy-Ozdemir: Department of Neurology, School of Medicine, Koç University, Istanbul, Turkey.
Ann Neurol. 2018 Jan;83(1):61-73. doi: 10.1002/ana.25122.
Glycogen in astrocyte processes contributes to maintenance of low extracellular glutamate and K concentrations around excitatory synapses. Sleep deprivation (SD), a common migraine trigger, induces transcriptional changes in astrocytes, reducing glycogen breakdown. We hypothesize that when glycogen utilization cannot match synaptic energy demand, extracellular K can rise to levels that activate neuronal pannexin-1 channels and downstream inflammatory pathway, which might be one of the mechanisms initiating migraine headaches.
We suppressed glycogen breakdown by inhibiting glycogen phosphorylation with 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and by SD.
DAB caused neuronal pannexin-1 large pore opening and activation of the downstream inflammatory pathway as shown by procaspase-1 cleavage and HMGB1 release from neurons. Six-hour SD induced pannexin-1 mRNA. DAB and SD also lowered the cortical spreading depression (CSD) induction threshold, which was reversed by glucose or lactate supplement, suggesting that glycogen-derived energy substrates are needed to prevent CSD generation. Supporting this, knocking down the neuronal lactate transporter MCT2 with an antisense oligonucleotide or inhibiting glucose transport from vessels to astrocytes with intracerebroventricularly delivered phloretin reduced the CSD threshold. In vivo recordings with a K -sensitive/selective fluoroprobe, Asante Potassium Green-4, revealed that DAB treatment or SD caused a significant rise in extracellular K during whisker stimulation, illustrating the critical role of glycogen in extracellular K clearance.
Synaptic metabolic stress caused by insufficient glycogen-derived energy substrate supply can activate neuronal pannexin-1 channels as well as lower the CSD threshold. Therefore, conditions that limit energy supply to synapses (eg, SD) may predispose to migraine attacks, as suggested by genetic studies associating glucose or lactate transporter deficiency with migraine. Ann Neurol 2018;83:61-73.
星形胶质细胞突起中的糖原有助于维持兴奋性突触周围细胞外谷氨酸和 K 浓度的低水平。睡眠剥夺（SD）是常见的偏头痛触发因素，它会诱导星形胶质细胞的转录变化，减少糖原分解。我们假设，当糖原利用不能满足突触能量需求时，细胞外 K 可以上升到激活神经元连接蛋白-1 通道和下游炎症途径的水平，这可能是引发偏头痛的机制之一。
我们通过抑制糖原磷酸化用 1,4-二脱氧-1,4-亚氨基-D-阿拉伯糖醇（DAB）和 SD 来抑制糖原分解。
DAB 导致神经元连接蛋白-1 大孔开放和下游炎症途径的激活，表现为半胱天冬酶-1 切割和 HMGB1 从神经元释放。6 小时的 SD 诱导连接蛋白-1 mRNA。DAB 和 SD 也降低了皮质扩散性抑制（CSD）的诱导阈值，用葡萄糖或乳酸补充可以逆转这一结果，这表明需要糖原衍生的能量底物来防止 CSD 的产生。支持这一点，用反义寡核苷酸敲低神经元乳酸转运体 MCT2 或用脑室内给予根皮苷抑制葡萄糖从血管向星形胶质细胞的转运，降低了 CSD 阈值。用 K 敏感/选择性荧光探针 Asante Potassium Green-4 进行的体内记录显示，DAB 处理或 SD 在胡须刺激时导致细胞外 K 显著升高，说明了糖原在细胞外 K 清除中的关键作用。
由于缺乏糖原衍生的能量底物供应而导致的突触代谢应激可以激活神经元连接蛋白-1 通道，并降低 CSD 阈值。因此，限制突触能量供应的条件（如 SD）可能容易引发偏头痛发作，正如与葡萄糖或乳酸转运体缺乏相关的遗传研究所表明的那样。Ann Neurol 2018;83:61-73.
