Mechanisms of neuronal survival and degeneration are central to the understanding of neurodegenerative diseases. Cerebellar granule neurons (CGN) have been widely used as a model system for studying these mechanisms. It is well known that the survival of rat CGN in culture is promoted by supra physiological extracellular potassium ion concentrations ([K⁺]_o), but whether mouse CGN have a similar requirement for elevated [K⁺]_o may depend upon the mouse strain [1]. To add to this body of knowledge, we tested the effect of [K⁺]_o on the survival of CGN from Swiss-Webster mice, a common laboratory strain. CGN were prepared from cerebella of 4-5 day old mouse pups and cultured for 5 days in Modified Eagle’s Medium (MEM) with 25 mM [K⁺] and fetal bovine serum. The medium was then changed to serum-free MEM with 5.6 mM [K⁺], or 25 mM [K⁺] as control. Cell viability was assayed 24 hours later by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide reduction (MTT assay), and was 48 ±1.3% (mean±sem) in 5.6 mM [K⁺]_o compared to 25 mM [K⁺]_o (1.7% sem; p<0.0001, t test). CGN and other cell types have been reported to be protected by potassium channel blockers, with different blockers being effective in different cell types. We tested the protective effects of potassium channel blockers on Swiss-Webster CGN and found a limited degree of protection in 5.6 mM [K⁺]_o by 2 mM 4-aminopyridine (4-AP; 63±2.2%; p<0.001), 2 mM tetraethylammonium (TEA; 58±1.7%; p<0.01) and 1 mM Ba²⁺ (66±1.3%; p<0.001) by ANOVA vs 5.6 mM [K⁺]_o alone (47±1.0%). The protective effect of these blockers was additive; survival in 5.6 mM [K⁺]_o plus 4-AP, TEA and Ba²⁺ (98±2.2%) was equivalent to survival in 25 mM [K⁺]_o without blockers (1.4% sem). The neuroprotective effect of elevated [K⁺]_o is reported to be attenuated by L-type Ca²⁺ channel blockers in rat CGN [2,3]. We found a similar effect of 2 μM nifedipine on Swiss-Webster CGN (78 ±1.8% survival); p<0.001 by ANOVA vs 25 mM [K⁺]_o (3.4% sem), but nifedipine did not attenuate the neuroprotective effect of potassium channel blockers (p>0.05 by ANOVA). Taken together, these results suggest that the survival of CGN depends on the total potassium permeability of the membrane rather than the activity of a particular type of potassium channel, and that the mechanism of neuroprotection by potassium channel blockers does not involve voltage-dependent influx of Ca²⁺. (Note: For results reported here, n≥18 from at least two separate experiments.)