Spontaneous neurotransmission: A form of neural communication comes of age

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Since its discovery by Bernard Katz and colleagues at the frog neuromuscular junction, spontaneous neurotransmitter release has never ceased to fascinate neurophysiologists. The initial observations of spontaneous events were considered within the general context of biological noise, and their functional implications were only guessed (Fatt & Katz, 1950). However, even during initial experiments, these random miniature synaptic release events were shown to trigger occasional action potentials in the muscle, suggesting a potential physiological impact of this form of neurotransmitter release (Fatt & Katz, 1950). In the intervening decades, the function and mechanism of these seemingly random neurotransmitter release events have continued to be a subject of extensive speculation. Yet, the question of why synapses, dedicated to information transfer and processing with high temporal and spatial precision, would give rise to random outbursts of neurotransmitter release and activity, has remained unanswered.
The advent of high‐resolution electrophysiology uncovered the ubiquity of this form of neurotransmission in multiple species, from invertebrates to vertebrates, including the mammalian brain. However, direct examination of spontaneous neurotransmission was hindered by the ability to manipulate it, due to limited insight into the properties of the release machinery and synaptic transmission in single synapses. This critical insight was gained during initial molecular manipulations of the release machinery via clostridial toxins or genetic models, which provided the first hints at a diversity of mechanisms that could give rise to spontaneous and action potential–evoked neurotransmission. In these studies, evoked release could be readily impaired by disruption of the soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE) machinery or Ca2+ sensors, while spontaneous release was more resilient to these manipulations (for review, see Kavalali, 2015). This suggested that spontaneous and evoked release could be regulated independently and that spontaneous release might serve its own function.
In the last decade, our group, as well as others, has initiated a systematic analysis of spontaneous neurotransmission to uncover its molecular regulation and synaptic function. This work has been enabled by the development of new methods for optical imaging of synaptic vesicle trafficking and visualization of synaptic transmission at single synaptic terminals. In this way, we could focus on examination of synaptic transmission at the level of individual synaptic contacts, single synaptic vesicles, and postsynaptic receptor clusters. When combined with these advanced functional tools, our increasing insight into the molecular organization of synaptic terminals brought this peculiar form of neuronal communication from the realm of speculation and assumptions into the territory of direct experimental inquiry. This endeavor led to several unexpected findings. Importantly, cross‐depletion experiments—where one form of neurotransmission can be selectively impaired—provided evidence for the independence of the two forms of neurotransmission and the potential diversity of vesicle populations giving rise to spontaneous and action potential–evoked neurotransmitter release. The findings from this work showed that spontaneous neurotransmitter release is driven by a vesicle population that preferentially recycles at rest independent of the vesicle pool that drives action potential–evoked release (Chung, Barylko, Leitz, Liu, & Kavalali, 2010; Fredj & Burrone, 2009; Sara, Virmani, Deak, Liu, & Kavalali, 2005). Several molecular mechanisms appear to work in parallel to make this apparent vesicle pool diversity possible. For instance, vesicular SNARE molecules vti1a, VAMP7, and to some extent VAMP4 selectively impact spontaneous release (Bal et al., 2013; Hua et al., 2011; Raingo et al., 2012; Ramirez, Khvotchev, Trauterman, & Kavalali, 2012), whereas complexins that interact with SNARE complexes augment evoked release but suppress spontaneous release in multiple systems (Huntwork & Littleton, 2007; Yang, Cao, & Sudhof, 2013).
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