Calcium modeling of spine apparatus-containing human dendritic spines demonstrates an "all-or-nothing" communication switch between the spine head and dendrite

Dendritic spines are highly dynamic neuronal compartments that control the synaptic transmission between neurons. Spines form ultrastructural units, coupling synaptic contact sites to the dendritic shaft and often harbor a spine apparatus organelle, composed of smooth endoplasmic reticulum, which is responsible for calcium sequestration and release into the spine head and neck. The spine apparatus has recently been linked to synaptic plasticity in adult human cortical neurons. While the morphological heterogeneity of spines and their intracellular organization has been extensively demonstrated in animal models, the influence of spine apparatus organelles on critical signaling pathways, such as calcium-mediated dynamics, is less well known in human dendritic spines. In this study we used serial transmission electron microscopy to anatomically reconstruct nine human cortical spines in detail as a basis for modeling and simulation of the calcium dynamics between spine and dendrite. The anatomical study of reconstructed human dendritic spines revealed that the size of the postsynaptic density correlates with spine head volume and that the spine apparatus volume is proportional to the spine volume. Using a newly developed simulation pipeline, we have linked these findings to spine-to-dendrite calcium communication. While the absence of a spine apparatus, or the presence of a purely passive spine apparatus did not enable any of the reconstructed spines to relay a calcium signal to the dendritic shaft, the calcium-induced calcium release from this intracellular organelle allowed for finely tuned "all-or-nothing" spine-to-dendrite calcium coupling; controlled by spine morphology, neck plasticity, and ryanodine receptors. Our results suggest that spine apparatus organelles are strategically positioned in the neck of human dendritic spines and demonstrate their potential relevance to the maintenance and regulation of spine-to-dendrite calcium communication. Author summaryDuring the past decade it has become increasingly clear that abnormal synaptic plasticity is a major hallmark of neurological and cognitive disorders. Developing a better understanding of the synaptic plasticity process, which describes the ability of neurons to adapt their contacts in an activity-dependent manner, will lead to improved treatment of many neurological and cognitive disorders. It is known that calcium dependent events such as synaptic transmission, intracellular calcium release, and calcium wave propagation, are required for many types of synaptic plasticity expression. However, the biological significance of these processes in neurons of the adult human cortex remains unknown. Due to technical limitations and ethical concerns, experimental data addressing this biologically and clinically relevant topic are not available. Therefore, we have implemented a computational model to study the intracellular calcium dynamics in realistic human dendritic spines based on detailed morphological reconstructions. With our model and simulations, we have established the morphological and biological requirements for the propagation of calcium from spines into the dendrites. Our results suggest a critical role for the calcium-storing spine apparatus organelle in regulating calcium homeostasis and propagation in human dendritic spines.