CALMODULIN GATES SPINE-TO-DENDRITE CALCIUM COUPLING BY ACTIVATING RYANODINE TYPE 3 RECEPTORS (RYR3)

Learning and plasticity are governed by calcium dynamics, which is tightly controlled in neurons by, for example, buffering by proteins such as calmodulin. Calmodulin itself controls the activity of plasma membrane Ca2+ ATPases (PMCA) and ryanodine receptors (RyR). The former extrude calcium from the cytosol to the extracellular space, and the latter are activated by cytosolic calcium, and release calcium from the endoplasmic reticulum (ER) to the cytosol. In CA1 pyramidal neurons, RyR2 (inhibited by calmodulin) and RyR3 (activated by calmodulin) are found in dendritic shafts and spines, respectively. Because of calmodulin abundance in the brain, most RyRs are constitutively bound to it. However, oxidation, observed in aging and neurodegeneration, lowers the affinity of calmodulin for its targets, changing calcium homeostasis.

We wanted to confirm that spine ER transduces calcium transients in healthy neurons and investigate the effect of higher oxidation levels accompanying old age on the spatial and temporal specificity of Ca transients.

We developed a multi-compartment stochastic reaction-diffusion model of signaling pathways underlying calcium regulation in a 51 um long apical dendrite of a CA1 pyramidal neuron with a spine with and without the spine ER (spine apparatus). For the old age condition, we also simulated over-expression of RyRs, L-type calcium channels, increased cytoplasmic calcium buffering, and lowered the affinity of calmodulin for its targets.

RyR3, L-type calcium channel, and IP3 receptor activation was crucial in the transduction of calcium signals from the spine to the dendrite. Higher calmodulin oxidation caused lower RyR3 activation abolished this effect.