AMPK-mediated potentiation of GABAergic signalling drives hypoglycaemia-provoked spike-wave seizures.
AMPK-mediated potentiation of GABAergic signalling drives hypoglycaemia-provoked spike-wave seizures.
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DOI：
10.1093/brain/awac037
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发表时间：
2022-07-29
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代谢调节神经元活动并调节癫痫发作的发生。在这里，使用两个啮齿动物模型的失神癫痫，我们表明，低血糖增加棘波发作的发生。然后，我们表明，选择性地破坏糖酵解在丘脑，一个结构牵连缺席癫痫，是足以增加棘波癫痫发作。我们认为，丘脑AMP活化蛋白激酶（细胞能量应激的传感器和代谢型GABAB受体功能的增强剂）的激活是低血糖诱导的棘波癫痫发作的重要驱动因素。我们发现，AMP激活的蛋白激酶增强突触后GABAB受体介导的电流在丘脑皮质神经元和加强癫痫样网络活动诱发丘脑脑片。选择性丘脑AMP激活蛋白激酶激活也增加棘波癫痫发作。最后，全身给予二甲双胍（一种AMP活化蛋白激酶激动剂）和常见的糖尿病治疗，显著增加了棘波癫痫发作。这些结果推进了几十年的观察，即葡萄糖代谢调节丘脑皮质回路兴奋性，表明AMP激活的蛋白激酶和GABAB受体的协同作用足以引起棘波癫痫发作。低血糖是失神发作的一个既定诱因。Salvati等研究了这种联系的潜在机制，并表明丘脑AMPK-细胞内ATP的细胞传感器-的激活通过增强GABA-B受体信号传导促进了失神癫痫大鼠模型中的棘波活动。
Metabolism regulates neuronal activity and modulates the occurrence of epileptic seizures. Here, using two rodent models of absence epilepsy, we show that hypoglycaemia increases the occurrence of spike-wave seizures. We then show that selectively disrupting glycolysis in the thalamus, a structure implicated in absence epilepsy, is sufficient to increase spike-wave seizures. We propose that activation of thalamic AMP-activated protein kinase, a sensor of cellular energetic stress and potentiator of metabotropic GABAB-receptor function, is a significant driver of hypoglycaemia-induced spike-wave seizures. We show that AMP-activated protein kinase augments postsynaptic GABAB-receptor-mediated currents in thalamocortical neurons and strengthens epileptiform network activity evoked in thalamic brain slices. Selective thalamic AMP-activated protein kinase activation also increases spike-wave seizures. Finally, systemic administration of metformin, an AMP-activated protein kinase agonist and common diabetes treatment, profoundly increased spike-wave seizures. These results advance the decades-old observation that glucose metabolism regulates thalamocortical circuit excitability by demonstrating that AMP-activated protein kinase and GABAB-receptor cooperativity is sufficient to provoke spike-wave seizures. Hypoglycaemia is an established trigger for absence seizures. Salvati et al. investigate the mechanism underlying this link, and show that activation of thalamic AMPK—a cellular sensor of intracellular ATP—promotes spike-wave activity in a rat model of absence epilepsy by potentiating GABA-B receptor signalling.
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