The effect of noise on CaMKII activation in a dendritic spine during LTP induction.

Activation of calcium-calmodulin dependent protein kinase II (CaMKII) during induction of long-term potentiation (LTP) is a series of complicated stochastic processes that are affected by noise. There are two main sources of noise affecting CaMKII activation within a dendritic spine. One is the noise associated with stochastic opening of N-methyl-d-aspartate (NMDA) receptor channels and the other is the noise associated with the stochastic reaction-diffusion kinetics leading to CaMKII activation. Many models have been developed to simulate CaMKII activation, but there is no fully stochastic model that studies the effect of noise on CaMKII activation. Here we construct a fully stochastic model to study these effects. Our results show that noise has important effects on CaMKII activation variability, with the effect from stochastic opening of NMDA receptor channels being 5-10 times more significant than that from stochastic reactions involving CaMKII. In addition, CaMKII activation levels and the variability of activation are greatly affected by small changes in NMDA receptor channel number at the synapse. One reason LTP induction protocols may require tetanic or repeated burst stimulation is that there is a need to overcome inherent variability to provide sufficiently large calcium signals through NMDA receptor channels; with meaningful physiological stimuli, noise may allow the calcium signal to exceed threshold for CaMKII activation when it might not do so otherwise.