Intrahippocampal infusion of an inhibitor of protein kinase A separates short- from long-term memory

Rats implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus were trained in one-trial step-down inhibitory (passive) avoidance, and tested for short- and long-term memory of this task at 1.5-3.0 and at 24 h from training, respectively. At various times after training (0, 22, 45, 90, 135 or 175 min) they received a 0.5 mu l infusion of the protein kinase A (PKA) inhibitor, KT5720 (0.1 or 0.5 mu g), or of its vehicle (20% dimethylsulfoxide in saline). At the higher dose, KT5720 inhibited PKA activity by 90%. KT5720 blocked long-term memory (LTM) when given either 0 or 175 min posttraining, and short-term memory (STM) when given 0, 22, 45 or 90 min post-training. Therefore, PKA plays a different role in the process of formation of the two types of memory. Its role in LTM may be related to the peak of PKA activity, and to the levels of its substrate, nuclear P-CREB, that have been described in a previous paper to occur at 0 and again at 3 h after training. The role of PKA in STM may well involve other substrates of the enzyme. This finding points to a cleavage between the mechanisms of STM and LTM formation. (C) 1999 Lippincott Williams & Wilkins.