The role of electrical and potassium (K +)-induced depolarisation on choline-acetyltransferase (ChAT) activity in human and mouse neocortical slices was studied. When 3 H -ACh release was evoked by two K + stimulations in human neocortex, the mean S 2/ S 1 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 S 2/ S 1 value in the absence of ChAT inhibitors reflected an increased ChAT activity at S 2 following K + depolarisation at S 1. When stimulated electrically, however, the S 2/ S 1 ratio in human neocortex was near unity and ocadaic acid remained without effect. In parallel experiments on mouse neocortical slices, the S 2/ S 1 ratio was near unity in both electrically or K +-evoked 3 H -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.