We have used a combined genetic and pharmacological approach to define the time course of the requirement for protein kinase A (PKA) and protein synthesis in long-term memory for contextual fear conditioning in mice. The time course of amnesia in transgenic mice that express R(AB) and have genetically reduced PKA activity in the hippocampus parallels that observed both in mice treated with inhibitors of PKA and mice treated with inhibitors of protein synthesis. This PKA- and protein synthesis-dependent memory develops between 1 hr and 3 hr after training. By injecting the protein synthesis inhibitor anisomycin or the PKA inhibitor Rp-cAMPs at various times after training, we find that depending on the nature of training, contextual memory has either one or two brief consolidation periods requiring synthesis of new proteins, and each of these also requires PKA. Weak training shows two time periods of sensitivity to inhibitors of protein synthesis and PKA, whereas stronger training exhibits only one. These studies underscore the parallel dependence of long-term contextual memory on protein synthesis and PKA and suggest that different training protocols may recruit a common signaling pathway in distinct ways.

Different Training Procedures Recruit Either One or Two Critical Periods for Contextual Memory Consolidation, Each of Which Requires Protein Synthesis and PKA