Spreading depolarizations (SDs) of gray matter occur in the brain, in different pathological conditions, and cause varying degrees of tissue damage depending on the extent of metabolic burden on the tissue. As might be expected for such large depolarizations, neurons exhibit bursts of action potentials as the wave propagates. However, the specific role of action potentials in SD propagation is unclear. This is potentially consequential, since sodium channel modulation has not been considered as a therapeutic target for SD-associated disorders, due to ambiguous experimental evidence. Using whole-cell electrophysiology and single-photon imaging in acute cortical slices from male C57Bl6 mice, we tested the effects of action potential blockade on SDs generated by two widely used induction paradigms. We found that action potential blockade using tetrodotoxin (TTX) restricted propagation of focally induced SDs, and significantly reduced the amplitude of neuronal depolarization, as well as its Ca2+ load. TTX also...