Migraine with aura is a common but poorly understood sensory circuit disorder. Monogenic models allow an opportunity to investigate its mechanisms, including spreading depolarization (SD), the phenomenon underlying migraine aura. Using fluorescent glutamate imaging, we show that awake mice carrying a familial hemiplegic migraine type 2 (FHM2) mutation have slower clearance during sensory processing, as well as previously undescribed spontaneous “plumes” of glutamate. Glutamatergic plumes overlapped anatomically with a reduced density of GLT-1a-positive astrocyte processes and were mimicked in wild-type animals by inhibiting glutamate clearance. Plume pharmacology and plume-like neural Ca²⁺ events were consistent with action-potential-independent spontaneous glutamate release, suggesting plumes are a consequence of inefficient clearance following synaptic release. Importantly, a rise in basal glutamate and plume frequency predicted the onset of SD in both FHM2 and wild-type mice, providing a novel mechanism in migraine with aura and, by extension, the other neurological disorders where SD occurs.

先兆偏头痛是一种常见但知之甚少的感觉回路障碍。单基因模型提供了研究其机制的机会，包括扩散去极化 (SD)，这是偏头痛先兆背后的现象。使用荧光谷氨酸成像，我们发现携带家族性偏瘫偏头痛 2 型 (FHM2) 突变的清醒小鼠在感觉处理过程中清除速度较慢，以及以前未描述的谷氨酸自发“羽流”。谷氨酸能羽在解剖学上与 GLT-1a 阳性星形胶质细胞突起密度降低重叠，并通过抑制谷氨酸清除在野生型动物中进行模拟。羽药理学和羽状神经Ca ²⁺事件与动作电位无关的自发谷氨酸释放一致，表明羽状物是突触释放后清除效率低下的结果。重要的是，基础谷氨酸和羽流频率的上升预测了 FHM2 和野生型小鼠的 SD 发作，为先兆偏头痛提供了一种新的机制，进而为其他发生 SD 的神经系统疾病提供了新的机制。