Initiation of migraine-related cortical spreading depolarization by hyperactivity of GABAergic neurons and NaV1.1 channels
Initiation of migraine-related cortical spreading depolarization by hyperactivity of GABAergic neurons and NaV1.1 channels
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DOI：
10.1172/jci142203
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发表时间：
2021-11-01
影响因子：
15.9
通讯作者：
Mantegazza, Massimo
中科院分区：
文献类型：
--
作者：
Chever, Oana;Zerimech, Sarah;Mantegazza, Massimo
扩散性去极化 (SD) 与偏头痛、癫痫、中风、创伤性脑损伤和蛛网膜下腔出血有关。然而，细胞起源和具体的分化机制尚不清楚。谷氨酸能活性的增加被认为是产生皮质扩散抑制（CSD）的关键因素，而皮质扩散抑制是偏头痛的一种病理机制。在这里，我们发现 Na(V)1.1（中间神经元的主要 Na+ 通道）的急性药理激活或光遗传学诱导的 GABA 能中间神经元的过度活跃足以通过尖峰产生的细胞外 K+ 积聚来点燃新皮质中的 CSD。 CSD 启动不需要 GABA 能突触传递或谷氨酸能突触传递。 CSD 并未在其他大脑区域产生，表明这是 CSD 启动的新皮质特异性机制。 Na(V)1.1 (SCN1A) 的功能获得性突变会导致家族性偏瘫型偏头痛 3 型 (FHM3)，这是一种先兆偏头痛的亚型，其中 CSD 是神经生理学相关因素。我们的结果提供了将 Na(V)1.1 功能增益与 FHM3 中 CSD 生成联系起来的机制。因此，我们揭示了 GABA 能中间神经元的过度活跃在 CSD 启动机制中的关键作用，这与 Na(v)1.1 FHM3 突变的病理机制有关，也可能与 SD 涉及的其他类型的偏头痛和疾病有关。
Spreading depolarizations (SDs) are involved in migraine, epilepsy, stroke, traumatic brain injury, and subarachnoid hemorrhage. However, the cellular origin and specific differential mechanisms are not clear. Increased glutamatergic activity is thought to be the key factor for generating cortical spreading depression (CSD), a pathological mechanism of migraine. Here, we show that acute pharmacological activation of Na(V)1.1 (the main Na+ channel of interneurons) or optogeneticinduced hyperactivity of GABAergic interneurons is sufficient to ignite CSD in the neocortex by spiking-generated extracellular K+ build-up. Neither GABAergic nor glutamatergic synaptic transmission were required for CSD initiation. CSD was not generated in other brain areas, suggesting that this is a neocortex-specific mechanism of CSD initiation. Gain-of-function mutations of Na(V)1.1 (SCN1A) cause familial hemiplegic migraine type-3 (FHM3), a subtype of migraine with aura, of which CSD is the neurophysiological correlate. Our results provide the mechanism linking Na(V)1.1 gain of function to CSD generation in FHM3. Thus, we reveal the key role of hyperactivity of GABAergic interneurons in a mechanism of CSD initiation, which is relevant as a pathological mechanism of Na(v)1.1 FHM3 mutations, and possibly also for other types of migraine and diseases in which SDs are involved.