Electrophysiological recordings of propagated compound action potentials (CAPs) and axonal Ca measurements using confocal microscopy were used to study the interplay between AMPA receptors and intracellullar Ca stores in rat spinal dorsal columns subjected to in vitro oxygen glucose deprivation (OGD). Removal of Ca or Na from the perfusate was protective after 30 but not 60 min of OGD. TTX was ineffective with either exposure, consistent with its modest effect on ischemic depolarization. In contrast, AMPA antagonists were very protective, even after 60 min of OGD where 0Ca/EGTA perfusate was ineffective. Similarly, blocking ryanodine-receptor mediated Ca mobilization from internal stores (0Ca+nimodipine or 0Ca+ryanodine), or IP3-dependent Ca release (group 1 mGluR block with 1-aminoindan-1,5-dicarboxylic acid, inhibition of phospholipase C with U73122, or IP3 receptor block with 2APB; each in 0Ca), were each very protective, with the combination resulting in virtually complete functional recovery after 1h OGD (97±32% CAP recovery vs. 4±6% in aCSF). AMPA induced a Ca rise in normoxic axons, which was greatly reduced by blocking ryanodine receptors. Our data therefore suggest a novel and surprisingly complex interplay between AMPA receptors and Ca mobilization from intracellular Ca stores. We propose that AMPA receptors may not only allow Ca influx from the extracellular space, but may also significantly influence Ca release from intra-axonal Ca stores. In dorsal column axons, AMPA receptor-dependent mechanisms appear to exert a greater influence on functional outcome following OGD than voltage-gated Na channels.