Abstract
Information processing in our brains depends on the exact timing of calcium (Ca2+)-activated exocytosis of synaptic vesicles (SVs) from unique release sites embedded within the presynaptic active zones (AZs). While AZ scaffolding proteins obviously provide an efficient environment for release site function, the molecular design creating such release sites had remained unknown for a long time. Recent advances in visualizing the ultrastructure and topology of presynaptic protein architectures have started to elucidate how scaffold proteins establish “nanodomains” that connect voltage-gated Ca2+ channels (VGCCs) physically and functionally with release-ready SVs. Scaffold proteins here seem to operate as “molecular rulers or spacers,” regulating SV-VGCC physical distances within tens of nanometers and, thus, influence the probability and plasticity of SV release. A number of recent studies at Drosophila and mammalian synapses show that the stable positioning of discrete clusters of obligate release factor (M)Unc13 defines the position of SV release sites, and the differential expression of (M)Unc13 isoforms at synapses can regulate SV-VGCC coupling. We here review the organization of matured AZ scaffolds concerning their intrinsic organization and role for release site formation. Moreover, we also discuss insights into the developmental sequence of AZ assembly, which often entails a tightening between VGCCs and SV release sites. The findings discussed here are retrieved from vertebrate and invertebrate preparations and include a spectrum of methods ranging from cell biology, super-resolution light and electron microscopy to biophysical and electrophysiological analysis. Our understanding of how the structural and functional organization of presynaptic AZs are coupled has matured, as these processes are crucial for the understanding of synapse maturation and plasticity, and, thus, accurate information transfer and storage at chemical synapses.
Highlights
Information processing in neural systems relies on accurate and modifiable communication between neurons at chemical synapses
For a detailed description and comparison of the different active zone (AZ) morphologies in various species and synapses, please refer to the following: Zhai and Bellen (2004), Ackermann et al (2015), and Slater (2015). All these different AZ designs probably possess a common concept for the ultrastructural organization at the presynaptic terminus, as they all possess an electron-dense projection at the presynaptic membrane, which contains the AZ protein cytomatrix, synaptic vesicles (SVs) that are tethered around these dense projections, and voltage-gated Ca2+ channels (VGCCs) that are positioned in the presynaptic membrane in close proximity to SVs
Decades of work have revealed a conserved subset of AZ scaffold proteins that collectively organize AZs functionally and structurally, and whose relative amounts and isoform spectrum might well be a major means of synapse diversification
Summary
Information processing in neural systems relies on accurate and modifiable communication between neurons at chemical synapses. For a detailed description and comparison of the different AZ morphologies in various species and synapses, please refer to the following: Zhai and Bellen (2004), Ackermann et al (2015), and Slater (2015) All these different AZ designs probably possess a common concept for the ultrastructural organization at the presynaptic terminus, as they all possess an electron-dense projection at the presynaptic membrane, which contains the AZ protein cytomatrix, SVs that are tethered around these dense projections, and VGCCs that are positioned in the presynaptic membrane in close proximity to SVs. Despite the apparent structural heterogeneity between the AZ ultrastructure of all these various synapse types, their presynaptic AZ sites support the docking of SVs at defined release sites on the presynaptic membrane. A simple and common concept of building the presynaptic AZ ultrastructure likely instructs the canonical design of release sites and helps define the lateral distances between SVs and VGCCs at these sites
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