Non-canonical glutamate signaling in a genetic model of migraine with aura

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. •FHM2 knockin mice have “plumes” of glutamate release in the cortex•Plumes are a consequence of inefficient glutamate clearance•A flurry of plumes precedes the onset of spreading depolarization at its origin•Spreading depolarization itself induces plumes as it propagates through the cortex Migraine is a common and debilitating neurological disorder whose underlying neurobiology is poorly understood. Parker et al. report “plumes” of glutamate release in a genetic model of migraine that are a consequence of inefficient glutamate clearance. Plumes also precede the onset of spreading depolarization, the physiological correlate of migraine aura.