Fig. 1: Synchronous, asynchronous, and spontaneous release at the single synapse level.

Schematic representation of the three principal modes of fast synaptic transmission at a single synapse. Presynaptically: (Left, Blue) Synchronous release is tightly coupled to an action potential (AP). It is triggered by high, localized calcium concentrations within a nanodomain near voltage-gated calcium channels (VGCCs). The low-affinity calcium sensors Synaptotagmin-1 (Syt-1) and Synaptotagmin-2 (Syt-2) along with the core SNARE complex, drive rapid vesicle fusion. (Middle, Green) Asynchronous release is also AP-evoked but occurs with a significant delay, lasting for tens to hundreds of milliseconds or longer. It is triggered by the accumulation of lower, residual “bulk” calcium in the terminal. This mode is mediated by a distinct set of high-affinity calcium sensors, including Synaptotagmin-3 (Syt-3), Synaptotagmin-7 (Syt-7), and Doc2α, and often engages the SNARE protein VAMP4. (Right, Yellow) Spontaneous release occurs stochastically in the absence of AP stimulation. It can be triggered by local calcium signals from stochastic VGCC openings or, critically, by calcium release from internal stores such as the endoplasmic reticulum. STIM proteins sense ER calcium depletion and promote store-operated calcium entry, further supporting spontaneous release. This overall process relies on distinct molecular machinery, including Doc2β and non-canonical SNAREs like VAMP7 and Vti1a. Postsynaptically: Spontaneous NMDAR activation can trigger the phosphorylation of eukaryotic elongation factor 2 (eEF2), a key step in regulating local protein synthesis. The (potential) activation of the downstream kinase CaMKII is indicated for AP-driven release modes. Traces represent timing of release events.