Abstract
Synapses maintain synchronous, asynchronous, and spontaneous modes of neurotransmission through distinct molecular and biochemical pathways. Traditionally a single synapse was assumed to have a homogeneous organization of molecular components both at the active zone and post-synaptically. However, recent advancements in experimental tools and the further elucidation of the physiological significance of distinct forms of release have challenged this notion. In comparison to rapid evoked release, the physiological significance of both spontaneous and asynchronous neurotransmission has only recently been considered in parallel with synaptic structural organization. Active zone nanostructure aligns with postsynaptic nanostructure creating a precise trans-synaptic alignment of release sites and receptors shaping synaptic efficacy, determining neurotransmission reliability, and tuning plasticity. This review will discuss how studies delineating synaptic nanostructure create a picture of a molecularly heterogeneous active zone tuned to distinct forms of release that may dictate diverse synaptic functional outputs.
Highlights
In the 1960s the canonical synaptic transmission pathway was established; neurotransmission is initiated by an action potential arriving at the presynaptic terminal, presynaptic calcium influx is triggered, synaptic vesicles fuse with the presynaptic membrane and release neurotransmitter (Katz, 1969; Südhof, 2013)
Studies conducted at the Drosophila neuromuscular junction as well as hippocampal synapses have demonstrated that a single active zone is capable of synchronous, asynchronous, and spontaneous release while some synapses exclusively execute spontaneous or evoked neurotransmission, creating a dynamic neuronal network dependent on distinct forms of neurotransmission (Atasoy et al, 2008; Melom et al, 2013; Peled et al, 2014; Reese and Kavalali, 2016)
Fluorescence imaging experiments in conjunction with electrophysiology have shown that Vps10p-tail-interactor-1a containing vesicles traffic in the absence of activity and vesicle-associated membrane protein 7 (VAMP7) containing vesicles preferentially traffic in response to resting calcium signals, both v-SNAREs drive spontaneous release (Hua et al, 2011; Ramirez et al, 2012; Bal et al, 2013; to see a full list of SNAREs associated with the synaptic vesicle proteome; see Takamori et al, 2006)
Summary
The fundamental reason we study the synapse is to understand how one neuron influences its targets To elucidate this process, we must consider how synaptic efficacy is shaped by multiple molecular pathways and different modes of neurotransmission. The size of the readily releasable pool, which includes vesicles docked at the active zone that fuse first in response to stimulation, and the fusion propensity of each synaptic vesicle dictates this release probability and synaptic strength (Rey et al, 2015; Chanaday and Kavalali, 2018) This view of synaptic strength and synaptic vesicle organization focused solely on evoked neurotransmission assumes a rather homogeneous synaptic vesicle pool and homogeneous organization of the active zone. It excludes other modes of neurotransmission and how their distinct functional roles may shape, guide, or determine synaptic efficacy
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