Cortical spreading depression (CSD) is considered a potential cause of migraines with an aura, but is not exclusive to migraines. Astrocytes are not only supporting cells for neurons, and the role of astrocytes in migraine with CSD has recently received increasing attention.

Astrocyte endfoot swelling is a characteristic of CSD, and neurons are not similarly altered. Astrocyte endfoot swelling, resulting in perivascular space closure, affects neuroinflammation clearance by the glymphatic system.

Astrocytic endfoot swelling during CSD is primarily due to K+ influx and abnormally active Ca2+ signaling. AQP-4 only mediates the process of K+ influx and plays a little role as an aquaporin.

Astrocytes are a double-edged sword, with protective effects on neurons during the early stages of CSD. Astrocytes provide neurons with energy support and clear K+ and glutamate from synaptic gaps. With CSD progression, astrocyte dysfunction drives the CSD spread.