INTRODUCTION: Roughly half of dendritic spines, which comprise post-synaptic site of excitatory synapses, contain endoplasmic reticulum (spine apparatus, SA). Ryanodine receptors (RyR), which are activated by calcium (Ca), located in spine necks acts as a transducer of Ca signals from the spine to the dendrite. Out of the 3 types of RyR RyR2 are inhibited by calmodulin (Cam) and RyR3 are activated by Cam, which is one of the most abundant proteins in the brain. In control conditions in the brain both types of RyR are most likely constitutively bound to Cam. However, with higher oxidation levels Cam affinity for RyR is much lower. Dendrites of CA1 pyramidal neurons contain RyR2 and SA contain RyR3.

AIM(S): We wanted to confirm that SA acts as a transducer of Ca transients in control conditions and investigate the effect of higher oxidation levels accompanying old age on spatial and temporal specificity of Ca transients.

METHOD(S): We developed a multi-compartment stochastic reaction-diffusion model of signaling pathways underlying Ca regulation and Ca-induced Ca release in a 51 um long apical dendrite of a CA1 pyramidal neuron. For the condition of old age, which is accompanied by higher oxidation levels, we over-expressed RyRs, lowered activity of Ca extrusion pumps in the plasma membrane, doubled Ca buffering, and lowered cam affinity for RyR.

RESULTS: In control conditions only spines containing SA allowed for transduction of Ca transients from the spine to the dendrite. Spatial extent of those transients was symmetrical and reached roughly 5 um. In old age condition both types of spines allowed for transduction of Ca transients, which were also prolonged. Ca transients originating in spines without SA had spatial extent of 5 um. In old age condition spatial extent of Ca transients originating in spines with SA was doubled.

CONCLUSIONS: Calmodulin controls spatial and temporal specificity of calcium transients by inhibiting RyR2 receptors.