Impaired K + binding to glial migraine

Glutamate is the major excitatory neurotransmitter in the central nervous system, and altered brain excitability caused by disturbed glutamate homeostasis plays a role in various paroxysmal neurological disorders1–3. Speci cally, glutamate is a potent trigger of cortical spreading depression (CSD), the electrophysiological correlate of migraine aura4, and imbalance of glutamate release and clearance has been shown to underlie hemiplegic migraine (HM), a severe monogenic subtype of migraine with transient hemiparesis and other aura symptoms5,6. EAAT1 is a glial glutamate transporter that contributes to glutamate clearance in the cerebral cortex, cerebellum, diencephalon and caudal brainstem7. Genetic variation in SLC1A3 – the gene encoding EAAT1 has been linked to several neurological disorders with partially overlapping clinical features8–11. In 2005, Jen et al. reported a SLC1A3 missense mutation in a child with a complex syndrome comprising episodic ataxia, prolonged hemiplegia with migraine and seizures8. Here, we searched for and identi ed a novel heterozygous SLC1A3 mutation in a young man with a similar but less severe clinical phenotype with recurrent episodes of migrainous headache accompanied by transient hemiparesis. To characterize the functional e ects of the newly identi ed mutation on transporter function and compare them with results on other SLC1A3 mutations, we used both electrophysiology and biochemistry.