Activity-dependent inhibitory gating in molecular signaling cascades induces a novel form of intermediate-term synaptic facilitation in Aplysia californica

Mechanistically distinct forms of long-lasting plasticity and memory can be induced by a variety of different training patterns. Although several studies have identified distinct molecular pathways that are engaged during these different training patterns, relatively little work has explored potential interactions between pathways when they are simultaneously engaged in the same neurons and circuits during memory formation. Aplysia californica exhibits two forms of intermediate-term synaptic facilitation (ITF) in response to two different training patterns: (1) repeated trial (RT) ITF (induced by repeated tail nerve shocks [TNSs] or repeated serotonin [5HT] application) and (2) activity-dependent (AD) ITF (induced by sensory neuron activation paired with a single TNS or 5HT pulse). RT-ITF requires PKA activation and de novo protein synthesis, while AD-ITF requires PKC activation and has no requirement for protein synthesis. Here, we explored how these distinct molecular pathways underlying ITF interact when both training patterns occur in temporal register (an “Interactive” training pattern). We found that (1) RT, AD, and Interactive training all induce ITF; (2) Interactive ITF requires PKC activity but not de novo protein synthesis; and (3), surprisingly, Interactive training blocks persistent PKA activity 1 h after training, and this block is PKC-independent. These data support the hypothesis that sensory neuron activity coincident with the last RT training trial is sufficient to convert the molecular signaling already established by RT training into an AD-like molecular phenotype.