Intracellular Ca²⁺ Release and Synaptic Plasticity: A Tale of Many Stores

Ca²⁺ is an essential trigger for most forms of synaptic plasticity. Ca²⁺ signaling occurs not only by Ca²⁺ entry via plasma membrane channels but also via Ca²⁺ signals generated by intracellular organelles. These organelles, by dynamically regulating the spatial and temporal extent of Ca²⁺ elevations within neurons, play a pivotal role in determining the downstream consequences of neural signaling on synaptic function. Here, we review the role of three major intracellular stores: the endoplasmic reticulum, mitochondria, and acidic Ca²⁺ stores, such as lysosomes, in neuronal Ca²⁺ signaling and plasticity. We provide a comprehensive account of how Ca²⁺ release from these stores regulates short- and long-term plasticity at the pre- and postsynaptic terminals of central synapses.