(612g) Modeling to Memory: Understanding the Molecular Mechanisms of Short Term Memory

Learning and memory is thought to arise from dynamic changes in the connective strength of neuronal synaptic junctions. In the hippocampus (declarative memory) these changes occur on incredibly short timescales (seconds) and are mediated by protein signal transduction networks in specialized structures called synaptic spines. Many of the proteins involved in these networks have been identified, yet the dynamics of interactions and spatial localization of these proteins have yet to be fully described. Using a variety of computational techniques we have recently sought to quantitatively describe the regulation of proteins and the dynamic tuning of protein networks in response to a variety of frequency inputs that are critical in memory induction.

In excitatory neurons, dynamic changes in the strength of synaptic connections occur when calcium ions (Ca2+) flux through NMDA receptors and bind the Ca2+-sensor calmodulin (CaM). Ca2+/CaM, in turn, activates enzymes that induce actin polymerization, receptor trafficking, and transcription factor regulation. Our recent work has focused on how competition for a limited resource (such as Ca²⁺/CaM), can tune the activation of downstream proteins to respond to varying input frequencies. One prediction from the initial model suggested that downstream protein activation profiles may strongly depend on the identity and concentration of proteins that constitute the competitive pool. However, we have recently found that competition and signaling cross-talk can confer robustness in signaling outcomes with important implications in both normal and disease states.