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Calcium/calmodulin dependent Protein Kinase II (CaMKII) is critically involved in early phase Long Term Potentiation, a physiological correlate of learning and memory. CaMKII translocates to activated synapses within minutes after stimulation and modulates synaptic strengths once there. We want to quantitatively understand this translocation process through computer simulation of its observed features. Experimentally, the mobility of CaMKII can be studied by Fluorescence Recovery after Photobleaching (FRAP) of a small volume in dendrites of hippocampal neurons expressing Green Fluorescent Protein (GFP)-CaMKII fusions. Computationally, we are developing our simulation model in SMOLDYN, a program that models and tracks single molecule Brownian dynamics at the Smoluchowski level of approximation.

Since May 14th, I have been working on the initial phase of model development with Dr. Shahid Khan in the Laboratory of Neurobiology. Our aims were three fold: i) toset up basic models of dendritic spines in SMOLDYN and validate our methodologies of simulation and data analysis; ii) to optimize parameters used in FRAP experiments using simulated FRAP results; iii) to study in simulation the mobility of CaMKII in dendrites in the absence of chemical reactions. For i), I constructed a basic spine model in SMOLDYN with a hemispherical head, a cylindrical neck, and a cylindrical dendrite of realistic dimensions and wrote a suite of scripts in MATLAB for data analysis. I validated our methodology by showing that after photobleaching fluorescent CaMKII in the spine head, the half lifetime (t1/2) of recovery in the bleached region is inversely related to the spine neck cross-section area. For ii), I found that repeated photobleaching over 0.4 seconds, a common setting in our FRAP experiments, increased t1/2 of recovery by ~30% and decreased the extent of recovery by ~20% in the bleached region when compared to photobleaching over several milliseconds. I also found that partial photobleaching below 35% produces recovery curves less distinct from the background fluctuation and makes measurement more difficult. For iii), I showed that spines trap

CaMKII diffusing along the dendrite and render the diffusion anomalous, where the spatial variance of CaMKII concentration profile along the dendrite increases nonlinearly with time, in accordance to published literature. Preliminary data also suggest that the apparent diffusion coefficient of CaMKII varies in different dendrites in an order of magnitude, which may reflect age dependent changes in CaMKII aggregation.

Last updated November 16, 2007