The sensory-motor neuron synapse of Aplysia is an excellent model system for investigating the biochemical changes underlying memory formation. In this system, training that is separated by rest periods (spaced training) leads to persistent changes in synaptic strength that depend on biochemical pathways that are different from those that occur when the training lacks rest periods (massed training). Recently, we have shown that in isolated sensory neurons, applications of serotonin, the neurotransmitter implicated in inducing these synaptic changes during memory formation, lead to desensitization of the PKC Apl II response, in a manner that depends on the method of application (spaced versus massed). Here, we develop a mathematical model of this response in order to gain insight into how neurons sense these different training protocols. The model was developed incrementally, and each component was experimentally validated, leading to two novel findings: First, the increased desensitization due to PKA-mediated heterologous desensitization is coupled to a faster recovery than the homologous desensitization that occurs in the absence of PKA activity. Second, the model suggests that increased spacing leads to greater desensitization due to the short half-life of a hypothetical protein, whose production prevents homologous desensitization. Thus, we predict that the effects of differential spacing are largely driven by the rates of production and degradation of proteins. This prediction suggests a powerful mechanism by which information about time is incorporated into neuronal processing.
Memories are among an individual's most cherished possessions. One factor that has been shown to exert a powerful influence on memory formation is the pattern of training. Learning trials distributed over time have been shown to consistently produce longer lasting memories than trials distributed over short intervals, in every organism in which this has been studied. This observation has been investigated particularly well in the marine mollusk Aplysia californica. The nervous system of Aplysia is simple and well characterized, yet capable of forming memories, making it an ideal system for the study of learning and memory. Currently, we have a detailed understanding of memory formation in Aplysia at the cellular level. However, there remain many unanswered questions at the molecular level, particularly concerning how the effects of different patterns of learning are mediated. We have developed a mathematical model of a molecular signaling pathway known to underlie memory formation in Aplysia. Our model suggests that the rates of synthesis and degradation of proteins involved in memory regulation are essential for neurons of Aplysia to respond differentially to spaced and massed training. We were able to experimentally validate these findings, thus providing significant evidence for this model, which might underlie memory formation in more complex animals.