Synaptic terminals can release neurotransmitter by spontaneous vesicle fusion that is independent of presynaptic action potentials.
The traditional view of spontaneous neurotransmitter release suggests that spontaneous events occur randomly in the absence of stimuli owing to low-probability conformational changes in the vesicle fusion machinery.
Recent studies have identified key distinctions between the synaptic vesicle fusion machineries that perform spontaneous versus evoked neurotransmitter release.
In mammalian hippocampal synapses and at the Drosophila melanogaster neuromuscular junction, spontaneous and evoked neurotransmitter release events show some spatial segregation and activate distinct populations of postsynaptic receptors.
Segregation of spontaneous neurotransmission enables selective neuromodulation that is independent of evoked release.
In mammalian hippocampal synapses and at the D. melanogaster neuromuscular junction, spontaneous release events activate specific postsynaptic signal transduction cascades that maintain synaptic efficacy or regulate structural plasticity and synaptic development.
Novel strategies that selectively target spontaneous release events are needed to address whether spontaneous release can signal independently during ongoing activity in intact neuronal circuits.
Fast synaptic communication in the brain requires synchronous vesicle fusion that is evoked by action potential-induced Ca2+ influx. However, synaptic terminals also release neurotransmitters by spontaneous vesicle fusion, which is independent of presynaptic action potentials. A functional role for spontaneous neurotransmitter release events in the regulation of synaptic plasticity and homeostasis, as well as the regulation of certain behaviours, has been reported. In addition, there is evidence that the presynaptic mechanisms underlying spontaneous release of neurotransmitters and their postsynaptic targets are segregated from those of evoked neurotransmission. These findings challenge current assumptions about neuronal signalling and neurotransmission, as they indicate that spontaneous neurotransmission has an autonomous role in interneuronal communication that is distinct from that of evoked release.
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The author declares no competing financial interests.
- Docked vesicles
Synaptic vesicles that are tethered to the presynaptic membrane or the active zone structure. According to current views, not all docked vesicles are fully primed for fusion and release of neurotransmitter.
- Primed vesicles
Vesicles that are docked and that have advanced through all the necessary molecular rearrangements of the SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor) fusion machinery; that is, vesicles waiting for the influx of Ca2+ ions to trigger fusion. According to the current view, vesicle priming requires partial or full assembly of the SNARE complex, as well as interaction of SNAREs with other key fusion proteins, such as MUNC18, MUNC13 and other components of the presynaptic active zone.
- Super-resolution microscopy
A form of light microscopy that achieves a spatial resolution of 50–100 nm, which is beyond the limit set by diffraction; it includes stimulated emission depletion microscopy (STED), photoactivated localization microscopy (PALM) and stochastic optical reconstruction microscopy (STORM).
- Total internal reflection fluorescence microscopy
A high-resolution fluorescence microscopy technique that takes advantage of a laser-induced evanescent wave of fluorescence emission which is very close to the interface of two media that have different refractive indices.
- Ribbon synapses
Synapses characterized by an electron-dense ribbon or bar in the presynaptic terminal. The ribbon is commonly oriented at a right angle to the membrane and sits just above an evaginated ridge. It is thought that the ribbons help to guide vesicles to the release sites. Ribbon synapses are commonly found in the retina and cochlea of vertebrates.
- Synaptic scaling
Upscaling or downscaling of the quantal amplitude of all synapses onto a postsynaptic neuron in response to long-lasting changes in neuronal activity.
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Kavalali, E. The mechanisms and functions of spontaneous neurotransmitter release. Nat Rev Neurosci 16, 5–16 (2015). https://doi.org/10.1038/nrn3875
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