Molecular Underpinnings of Synaptic Vesicle Pool Heterogeneity

Abstract

Neuronal communication relies on chemical synaptic transmission for information transfer and processing. Chemical neurotransmission is initiated by synaptic vesicle fusion with the presynaptic active zone resulting in release of neurotransmitters. Classical models have assumed that all synaptic vesicles within a synapse have the same potential to fuse under different functional contexts. In this model, functional differences among synaptic vesicle populations are ascribed to their spatial distribution in the synapse with respect to the active zone. Emerging evidence suggests, however, that synaptic vesicles are not a homogenous population of organelles, and they possess intrinsic molecular differences and differential interaction partners. Recent studies have reported a diverse array of synaptic molecules that selectively regulate synaptic vesicles' ability to fuse synchronously and asynchronously in response to action potentials or spontaneously irrespective of action potentials. Here we discuss these molecular mediators of vesicle pool heterogeneity that are found on the synaptic vesicle membrane, on the presynaptic plasma membrane, or within the cytosol and consider some of the functional consequences of this diversity. This emerging molecular framework presents novel avenues to probe synaptic function and uncover how synaptic vesicle pools impact neuronal signaling.

Calcium dependence of spontaneous neurotransmitter release

“…Differences in synaptic protein isoforms are well recognized (Geppert et al, 1994;Sun, Jianyuan, et al, 2007) and are a putative mechanism to explain why VACCs trigger spontaneous release at inhibitory but not excitatory synapses. Since VACCs trigger evoked release at both types of synapse, this explanation would also necessitate differences in synaptic vesicle protein composition for evoked and spontaneous release (Crawford & Kavalali, 2015), or that the same synaptic proteins mediate evoked and spontaneous release but through different molecular mechanisms (Dai et al, 2015).…”

“…The vesicle and target synaptic membrane contain a variety of proteins that participate in and regulate exocytosis (Takamori et al, 2006;Weingarten et al, 2014;Wilhelm et al, 2014). However, some of these vesicleassociated proteins have been shown to participate in trafficking of vesicles into segregated pools, indicating that vesicles may have distinct molecular identities related to their function as well as contribute to differences in Ca 21 dependence (Crawford & Kavalali, 2015;Deitcher et al, 1998;Hua, Liu, & Li, 1998;Tafoya et al, 2006;Washbourne et al, 2002;Yang, Udayasankar, Dunning, Chen, & Gillis, 2002). Here we discuss the molecular mechanisms that mediate the [Ca 21 ] i dependence of release (or lack thereof), and the controversies in the field as well as likely causes for these discrepancies.…”

Diverse modes of synaptic signaling, regulation, and plasticity distinguish two classes ofC. elegansglutamatergic neurons

“…However, unc-13 was essential for all VGLUT-pH responses in ASH, but unc-18 was not, whereas AWC ON was more strongly dependent on unc-18 relative to unc-13. Thus the synaptic requirement for unc-13 and unc-18 may differ across different synapses or conditions, even in cells in which both genes are expressed and active (Atwood and Karunanithi, 2002;Crawford and Kavalali, 2015;Kasai et al, 2012).…”

Complexin cooperates with Bruchpilot to tether synaptic vesicles to the active zone cytomatrix

“…In brp nude single mutants, in turn, the intact Cpx clamp would prevent slowed reloading from reducing the mini frequency. Alternatively, evoked and spontaneous transmission may use nonidentical SV pools regulated differentially at the molecular level (Crawford and Kavalali, 2015;Kaeser and Regehr, 2014;Melom et al, 2013).…”