Abstract
Synaptic active zone (AZ) contains multiple specialized release sites for vesicle fusion. The utilization of release sites is regulated to determine spatiotemporal organization of the two main forms of synchronous release, uni-vesicular (UVR) and multi-vesicular (MVR). We previously found that the vesicle-associated molecular motor myosin V regulates temporal utilization of release sites by controlling vesicle anchoring at release sites in an activity-dependent manner. Here we show that acute inhibition of myosin V shifts preferential location of vesicle docking away from AZ center toward periphery, and results in a corresponding spatial shift in utilization of release sites during UVR. Similarly, inhibition of myosin V also reduces preferential utilization of central release sites during MVR, leading to more spatially distributed and temporally uniform MVR that occurs farther away from the AZ center. Using a modeling approach, we provide a conceptual framework that unites spatial and temporal functions of myosin V in vesicle release by controlling the gradient of release site release probability across the AZ, which in turn determines the spatiotemporal organization of both UVR and MVR. Thus myosin V regulates both temporal and spatial utilization of release sites during two main forms of synchronous release.
Highlights
Neurotransmitter release is governed by the fusion of synaptic vesicles at specialized release sites at the synaptic active zone (AZ)
We recently found that MVR events exhibit spatial and temporal patterns of organization which are determined by the gradient of release site properties across the individual AZs
We previously showed that vesicleassociated molecular motor myosin V is a key regulator of release site refilling during synaptic activity by controlling vesicle anchoring and retention at the release sites
Summary
Neurotransmitter release is governed by the fusion of synaptic vesicles at specialized release sites at the synaptic active zone (AZ). The number, spatial distribution and temporal utilization of release sites are thought to play important roles in regulating synaptic transmission (Neher, 2010). Spatial Regulation of Release ranging from 2 to 18 per AZ (Tang et al, 2016; Maschi and Klyachko, 2017; Sakamoto et al, 2018) These release sites are distributed throughout the AZ with the nearest-neighbor distances of ∼80–100 nm, and co-localize with clusters of pre-synaptic docking factors (Tang et al, 2016). Release site usage is dynamically regulated: vesicle release preferentially occurs at more central release sites during low activity, but shifts away from AZ center toward more peripheral release sites during high-frequency stimulation (Maschi and Klyachko, 2017)
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