Defective glutamate and K⁺ clearance by cortical astrocytes in familial hemiplegic migraine type 2

Migraine is a common disabling brain disorder. A subtype of migraine with aura (familial hemiplegic migraine type 2: FHM2) is caused by loss-of-function mutations in α₂ Na⁺,K⁺ ATPase (α₂ NKA), an isoform almost exclusively expressed in astrocytes in adult brain. Cortical spreading depression (CSD), the phenomenon that underlies migraine aura and activates migraine headache mechanisms, is facilitated in heterozygous FHM2-knockin mice with reduced expression of α₂ NKA. The mechanisms underlying an increased susceptibility to CSD in FHM2 are unknown. Here, we show reduced rates of glutamate and K⁺ clearance by cortical astrocytes during neuronal activity and reduced density of GLT-1a glutamate transporters in cortical perisynaptic astrocytic processes in heterozygous FHM2-knockin mice, demonstrating key physiological roles of α₂ NKA and supporting tight coupling with GLT-1a. Using ceftriaxone treatment of FHM2 mutants and partial inhibition of glutamate transporters in wild-type mice, we obtain evidence that defective glutamate clearance can account for most of the facilitation of CSD initiation in FHM2-knockin mice, pointing to excessive glutamatergic transmission as a key mechanism underlying the vulnerability to CSD ignition in migraine.