By using a combination of Ca2+ imaging and current-clamp recording, we previously reported that action potential (AP) conduction is reliably observed from the soma to axonal terminals in cultured cortical neurons. To extend these studies, we evaluated Ca2+ influx evoked by Na+ APs as a marker of AP conduction under conditions that are expected to lower the conduction safety factor to explore mechanisms of axonal and dendritic excitability. As expected, reducing the extracellular Na+ concentration from 150 to approximately 60 mM decreased the amplitude of APs recorded in the soma but surprisingly did not influence axonal conduction, as monitored by measuring Ca2+ transients. Furthermore, reliable axonal conduction was observed in dilute (20 nM) tetrodotoxin (TTX), despite a similar reduction in AP amplitude. In contrast, the Ca2+ transient measured along dendrites was markedly reduced in low Na+, although still mediated by TTX-sensitive Na+ channels. Dendritic action-potential evoked Ca2+ transients were also markedly reduced in 20 nM TTX. These data provide further evidence that strongly excitable axons are functionally compartmentalized from weakly excitable dendrites. We conclude that modulation of Na+ currents or membrane potential by neurotransmitters or repetitive firing is more likely to influence neuronal firing before AP generation than the propagation of signals to axonal terminals. In contrast, the relatively low safety factor for back-propagating APs in dendrites would suggest a stronger effect of Na+ current modulation.