Calmodulin controls spatial and temporal specificity of calcium-induced calcium release

Calcium dynamics controls learning and memory. Changes in calcium-induced calcium release (CICR), which is caused by opening ryanodine receptors (RyR) located on endoplasmic reticulum (ER) membrane, have been implicated in neurodegenerative disorders, such as Alzheimers disease (AD), manifesting with disruptions in calcium homeostasis and signaling. Calmodulin, one of the most abundant proteins in the brain, inhibits RyR2, expressed in the dendrites of hippocampal CA1 neurons, with several reported consequences: relieving of this inhibition is responsible for heart failure, and enhancing calmodulin to RyR binding [1] alleviates cell loss and AD-like neuronal hyperexcitability. To investigate the role of calmodulin in aging and AD, we built a sophisticated reaction-diffusion model of a dendritic branch with ER. We showed that relieving inhibition of RyR2 by calmodulin increased spatial and temporal spread of calcium transients in the dendrite. This effect was also visible in a model of old age, where disinhibition of RyR2 increased spatial spread of calcium transients by a factor of 2, and disinhibition of RyR2 combined with increased concentration of calcium buffering molecules increased duration of calcium transients, likely contributing to the deficits in learning and memory observed in old age. Lower activation of plasma membrane calcium ATPase (PMCA), which is also activated by calmodulin and inhibited by {beta}-Amyloid oligomers, and not RyR2 disinhibition, led to the increase resting intracellular calcium concentration observed in AD. Overall, our research demonstrates that changes in calmodulin that are associated with AD and aging, by regulation of RyR2 and PMCA, underlie changes in calcium dynamics that cause deficits in learning and memory. Author summaryCalcium dynamics controls learning and memory. In neurons calcium dynamics is regulated by a complex system including calcium-permeable channels and extrusion pumps. The components of this system are regulated by calmodulin, which is enriched in the brain. We show that relieving calmodulin inhibition of calcium permeable channels, which accompanies aging, decreases spatial and temporal specificity of calcium release contributing to the deficits in learning and memory observed in old age. In contrast, calcium extrusion pumps that are activated by calmodulin, are likely responsible for increased resting intracellular calcium concentration observed in Alzheimers disease. In consequence, a novel role emerges for calmodulin, which in the brain is primarily considered a fast-acting calcium buffering molecule, as an important regulator in neuronal calcium dynamics underlying pathology.