Spreading depression (SD) is a temporary disruption of local ionic homeostasis that propagates slowly across the cortex.Spreading depolarisation associated with SD occurs in different types of stroke and may contribute to the initiation of migraine attack.NMDA receptor (NMDAR) antagonists are known to be the most effective drugs to suppress SD.So far, NMDAR antagonist are still perceived as unlikely candidate as anti-SD drug for migraine aura treatment because of their unacceptable side effects, but the NMDAR antagonist, memantine is now used chronically in elderly for Alzheimers and epilepsy patients and some subtype selective receptor antagonists may well be effective with reduced side effects.Using an efficient in vitro chick retinal SD model with imaging for NMDAR pharmacology, we have determined whether NMDAR antagonists, with different type NR2 subunit selectivity, can suppress spreading depolarization associated with SD in the chicken retina preparation.The results suggested NR2A plays a key role in mediating SD, indicating potential therapeutic benefit for NR2A-preferring antagonist to treat SD-related neurological diseases, e.g.migraine with alleviated side effect.