C57BL/6Nia and F1(B6xD2)Nia mice were tested on the Morris water maze task for 5 days followed by 12 days of testing on the place learning-set task (8 trials/day with each task). Mice were tested at 3, 14, and 25 months of age C57 mice, 25 months of age, were significantly impaired in both the Morris and place learning-set task probe trial performance compared to mice 3 months of age (p < 0.05). These aged C57 mice also demonstrated a significant reduction in membrane-bound hippocampal protein kinase C (PKC) activity (p < 0.05) with no significant change in cytosolic PKC activity. F1 mice, however, showed no effect of age on probe trial performance on the spatial learning tasks. In addition, in a comparison of C57 and F1 mice within each age group, F1 mice demonstrated superior learning performance which was accompanied by a significant elevation in PKC activity (p < 0.05). Spatial learning performance of both strains significantly correlated with membrane-bound PKC activity (p < 0.01). These data provide additional support for our previous hypothesis of an involvement of hippocampal PKC activity in spatial learning and suggest that the amount of membrane-bound PKC activity may be a determinant of age-related decline in spatial learning.