Abstract
The trigger for synaptic vesicle exocytosis is Ca2+, which enters the synaptic bouton following action potential stimulation. However, spontaneous release of neurotransmitter also occurs in the absence of stimulation in virtually all synaptic boutons. It has long been thought that this represents exocytosis driven by fluctuations in local Ca2+ levels. The vesicles responding to these fluctuations are thought to be the same ones that release upon stimulation, albeit potentially triggered by different Ca2+ sensors. This view has been challenged by several recent works, which have suggested that spontaneous release is driven by a separate pool of synaptic vesicles. Numerous articles appeared during the last few years in support of each of these hypotheses, and it has been challenging to bring them into accord. We speculate here on the origins of this controversy, and propose a solution that is related to developmental effects. Constitutive membrane traffic, needed for the biogenesis of vesicles and synapses, is responsible for high levels of spontaneous membrane fusion in young neurons, probably independent of Ca2+. The vesicles releasing spontaneously in such neurons are not related to other synaptic vesicle pools and may represent constitutively releasing vesicles (CRVs) rather than bona fide synaptic vesicles. In mature neurons, constitutive traffic is much dampened, and the few remaining spontaneous release events probably represent bona fide spontaneously releasing synaptic vesicles (SRSVs) responding to Ca2+ fluctuations, along with a handful of CRVs that participate in synaptic vesicle turnover.
Highlights
THE PHENOMENON OF SPONTANEOUS RELEASE AT THE SYNAPTIC BOUTONNeuronal communication relies on precisely timed synaptic vesicle exocytosis, which is typically triggered by a brief intracellular Ca2+ spike that follows action potentials (Südhof, 2004; Rizzoli, 2014)
We suggest a simple solution to this problem: two completely different pools of vesicles share the synaptic bouton—synaptic vesicles, which can respond to stimulation and act as spontaneously releasing synaptic vesicles (SRSVs) and constitutively releasing vesicles (CRVs), which are involved in constitutive membrane traffic and which are not responsive to stimulation
WHAT IS THE PURPOSE OF SPONTANEOUS RELEASE? We suggest that CRVs are, during the early development of the neuron, a pool of constitutively recycling membranes, which participate in the formation of synapses and synaptic vesicles
Summary
THE PHENOMENON OF SPONTANEOUS RELEASE AT THE SYNAPTIC BOUTONNeuronal communication relies on precisely timed synaptic vesicle exocytosis, which is typically triggered by a brief intracellular Ca2+ spike that follows action potentials (Südhof, 2004; Rizzoli, 2014). The vesicles releasing spontaneously in such neurons are not related to other synaptic vesicle pools and may represent constitutively releasing vesicles (CRVs) rather than bona fide synaptic vesicles.
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