UC San Diego

The long-term goal of this project is to develop a model to explain the critical time window involved in the pairing protocol used for the induction of long-term potentiation (LTP) and long-term depression (LTD). This requires a detailed analysis of dendritic Ca²⁺ dynamics in dendritic spines and an investigation of the Ca²⁺-mediated signal transduction cascades initiated by neural activity. The model drew upon experimental data from the literature and projects in this proposal concerning the biochemical reactions that occur in the spine following the influx of Ca²⁺. These measurements were incorporated into MCell, a Monte Carlo computer program that simulates sub-cellular signaling. MCell uses ray-tracing techniques to follow the random walk and interaction between diffusible molecules. The spatial profile of calcium-binding protein activation in hippocampal area CA1 dendritic spines of different shapes was studied using a 5 [Mu]m x 5 [Mu]m x 5 [Mu]m volume of hippocampal area CA1 neuropil from mouse that has been reconstructed to serve as the anatomical substrate of the simulations. This allowed simulations of neurotransmitter release and diffusion in the extracellular space as well as the ensuing influx of Ca²⁺ to be accurately modeled. The estimated [Ca²⁺] and Ca²⁺- bound CaM in small functional microdomains, such as in the postsynaptic density was also monitored in spines of varying shapes, sizes, and neck lengths. The model measured the response following an EPSP, an action potential, or combinations of both. Finally, the effects of pump localization on the shape and amplitude of calcium transients in dendritic spines were simulated, revealing that pump placement affects the decay time in spines