Competitive Tuning of Ca2+/Calmodulin-Activated Proteins Provides a Compensatory Mechanism for AMPA Receptor Phosphorylation in Synaptic Plasticity

<p><u>Introduction:</u> Dynamic changes in the strength of synaptic connections, known as synaptic plasticity, are thought to be fundamental to learning and memory. In excitatory neurons, synaptic plasticity occurs when calcium ions (Ca<sup>2+</sup>) flux through NMDA receptors and bind the Ca<sup>2+</sup>-sensor calmodulin (CaM). The activation of downstream Ca<sup>2+</sup>/CaM binding proteins (CBPs) is a function of the frequency of Ca<sup>2+</sup> flux, such that each CBP is preferentially “tuned” to different Ca<sup>2+</sup> input signals. We have recently reported that competition among CBPs for CaM binding is alone sufficient to recreate <em>in silico</em> the observed <em>in vivo</em> frequency-dependence of several CBPs. However, CBP activation may strongly depend on the identity and concentration of proteins that constitute the competitive pool; with important implications in the regulation of CBPs that are implicated in learning and memory disorders.</p>

<p><u>Methods:</u> We hypothesize that although perturbations may decrease activation of one CBP, increased activation of another CBP could compensate this loss, providing a homeostatic effect. Using computational models, we explore this compensatory mechanism by quantifying the effect of parameter perturbations on competitive tuning. We also extend our model to include AMPA receptor phosphorylation, a hallmark of synaptic plasticity.</p>

<p><u>Results and Conclusions:</u> Although knockout of the CaM buffer neurogranin causes a decrease in CaMKII activation, overall AMPAR phosphorylation levels are maintained by a concomitant increase in AC8 activation. In some instances, increases AMPAR phosphorylation is seen. Our results explain recent counter-intuitive results in neurogranin knockout mice, provide further evidence that competitive tuning is an important mechanism in synaptic plasticity, and suggest new experiments to test this hypothesis.</p>

<p>The data files may be opened in the Wolfram Mathematica program or viewed in read-only mode using the Wolfram CDF Player freely available at: <a href="http://www.wolfram.com/cdf-player/">http://www.wolfram.com/cdf-player/</a>.</p>