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The role of electrical and potassium (K+)-induced depolarisation on choline-acetyltransferase (ChAT) activity in human and mouse neocortical slices was studied. When [3H]-ACh release was evoked by two K+ stimulations in human neocortex, the mean S2/S1 ratio was significantly below unity. ChAT inhibitors, like bromo-acetylcholine and ocadaic acid, raised this ratio by 79 and 63%, respectively, suggesting that the diminished S2/S1 value in the absence of ChAT inhibitors reflected an increased ChAT activity at S2 following K+ depolarisation at S1. When stimulated electrically, however, the S2/S1 ratio in human neocortex was near unity and ocadaic acid remained without effect. In parallel experiments on mouse neocortical slices, the S2/S1 ratio was near unity in both electrically or K+-evoked [3H]-ACh release and was not altered by ChAT inhibition. ChAT activity following K+ depolarisation was also determined directly. ChAT activation in human neocortical slices was highest at 10 and 20 mM K+. ChAT activity in mouse neocortical tissue was not altered by K+ depolarisation. These results suggest that in human, but not in mouse, neocortex ChAT activity may be increased due to ongoing K+ depolarisation. This increase of ChAT activity supports a cholinergic degeneration hypothesis which has been entitled “autocannibalism” by Wurtman [TINS 15 (1992) 177]. [Copyright &y& Elsevier]