Ryanodine Receptor Activation Induces Long-Term Plasticity of Spine Calcium Dynamics

A key feature of signalling in dendritic spines is the synapse-specific transduction of short electrical signals into biochemical responses. Ca2+ is a major upstream effector in this transduction cascade, serving both as a depolarising electrical charge carrier at the membrane and an intracellular second messenger. Upon action potential firing, the majority of spines are subject to global back-propagating action potential (bAP) Ca2+ transients. These transients translate neuronal suprathreshold activation into intracellular biochemical events. Using a combination of electrophysiology, two-photon Ca2+ imaging, and modelling, we demonstrate that bAPs are electrochemically coupled to Ca2+ release from intracellular stores via ryanodine receptors (RyRs). We describe a new function mediated by spine RyRs: the activity-dependent long-term enhancement of the bAP-Ca2+ transient. Spines regulate bAP Ca2+ influx independent of each other, as bAP-Ca2+ transient enhancement is compartmentalized and independent of the dendritic Ca2+ transient. Furthermore, this functional state change depends exclusively on bAPs travelling antidromically into dendrites and spines. Induction, but not expression, of bAP-Ca2+ transient enhancement is a spine-specific function of the RyR. We demonstrate that RyRs can form specific Ca2+ signalling nanodomains within single spines. Functionally, RyR mediated Ca2+ release in these nanodomains induces a new form of Ca2+ transient plasticity that constitutes a spine specific storage mechanism of neuronal suprathreshold activity patterns.A combination of two-photon calcium imaging, electrophysiology, and modelling shows how ryanodine receptors (a type of intracellular calcium channel) generate a signalling nanodomain within individual dendritic spines, enabling compartmentalized plasticity of calcium dynamics.Author Summary: Experiences change neuronal circuits, and these circuit changes outlast the initial experiences. This means that, in neurons, the fast electrical activity encoding experiences needs to be transduced into longer-lived biochemical and structural changes. A key mediator between these two timescales of neuronal activity is the Ca2+ ion. Ca2+ serves both as an electric charge carrier mediating fast voltage changes at the membrane and as a second messenger activating intracellular signalling cascades. Even within the spatial confines of dendritic spines, the specialized domains of dendrites that receive synaptic connections, Ca2+ encodes a versatile array of specific functions. In this study, we first demonstrate that voltage-gated Ca2+ channels and ryanodine receptors, intracellular channels located on the membrane of the endoplasmic reticulum through which Ca2+ can be released into the cytosol, are electrochemically coupled in single dendritic spines. We identify how ryanodine receptors induce enhancement of the Ca2+ influx, mediated by the opening of voltage-gated Ca2+ channels, induced by action potentials in a compartmentalized, spine-specific manner. Within the femtoliter volume of a single spine, specificity of this route of Ca2+-signalling is achieved by a signalling nanodomain centred on the ryanodine receptor. Our work stresses the role of the ryanodine receptor not only as an ion channel releasing Ca2+ from the endoplasmic reticulum but also as a macromolecular complex generating specificity of Ca2+-signalling within the spatial constraints of a single spine.