Cortical spreading depression (CSD), a wave of depolarization followed by depression of cortical activity, is a pathophysiological process implicated in migraine with aura and various other brain pathologies, such as ischemic stroke and traumatic brain injury. To gain insight into the pathophysiology of CSD, we generated a mouse model for a severe monogenic subtype of migraine with aura, familial hemiplegic migraine type 3 (FHM3). FHM3 is caused by mutations in SCN1A, encoding the voltage-gated Na⁺ channel Na_V1.1 predominantly expressed in inhibitory interneurons. Homozygous Scn1a^L1649Q knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan. Heterozygous Scn1a^L1649Q knock-in mice compared with WT mice displayed a significantly enhanced susceptibility to CSD. We found L1649Q to cause a gain-of-function effect with an impaired Na⁺-channel inactivation and increased ramp Na⁺ currents leading to hyperactivity of fast-spiking inhibitory interneurons. Brain slice recordings using K⁺-sensitive electrodes revealed an increase in extracellular K⁺ in the early phase of CSD in heterozygous mice, likely representing the mechanistic link between interneuron hyperactivity and CSD initiation. The neuronal phenotype and premature death of homozygous Scn1a^L1649Q knock-in mice was partially rescued by GS967, a blocker of persistent Na⁺ currents. Collectively, our findings identify interneuron hyperactivity as a mechanism to trigger CSD.

中文翻译：

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过度兴奋的中间神经元在 Scn1a 偏头痛模型中触发皮质扩散抑制

皮质扩散抑制 (CSD) 是一种去极化波，然后是皮质活动抑制，是一种病理生理过程，与先兆偏头痛和各种其他脑部疾病（例如缺血性中风和创伤性脑损伤）有关。为了深入了解 CSD 的病理生理学，我们为具有先兆的严重单基因偏头痛亚型、家族性偏瘫偏头痛 3 型 (FHM3) 生成了小鼠模型。FHM3 是由SCN1A 中的突变引起的，编码电压门控 Na ⁺通道 Na _V 1.1，主要在抑制性中间神经元中表达。纯合Scn1a L1649Q^基因敲入小鼠过早死亡，而杂合小鼠寿命正常。杂合Scn1a ^L1649Q与 WT 小鼠相比，敲入小鼠对 CSD 的易感性显着增强。我们发现 L1649Q 会导致功能获得效应，导致 Na ⁺通道失活受损和斜坡 Na ⁺电流增加，导致快速尖峰抑制性中间神经元过度活跃。使用 K ⁺敏感电极的脑切片记录显示，杂合子小鼠 CSD 早期细胞外 K ⁺增加，可能代表中间神经元过度活跃和 CSD 起始之间的机制联系。^GS967是一种持久性 Na ⁺阻滞剂，部分挽救了纯合Scn1a ^L1649Q敲入小鼠的神经元表型和过早死亡电流。总的来说，我们的研究结果将中间神经元过度活跃确定为触发 CSD 的机制。