Presynaptic active zones in invertebrates and vertebrates

Ackermann, Frauke; Waites, Clarissa L.; Garner, Craig C.

doi:10.15252/embr.201540434

Cited by 121 publications

(125 citation statements)

References 157 publications

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“…However, at all synapses where AZM relationships have been examined by electron tomography, AZM macromolecules link the VM to the PM (2,11,12,14,27,37,(56)(57)(58)(59). This commonality, together with the high degree of homology of proteins involved in docking and priming at all synapses (60), suggests that our AZM-mediated variable force hypothesis (Fig. 6) for the regulation of priming at the frog's NMJ may have general applicability.…”

Section: Discussionmentioning

confidence: 85%

Variable priming of a docked synaptic vesicle

Jung

Szule

Marshall

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

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The priming of a docked synaptic vesicle determines the probability of its membrane (VM) fusing with the presynaptic membrane (PM) when a nerve impulse arrives. To gain insight into the nature of priming, we searched by electron tomography for structural relationships correlated with fusion probability at active zones of axon terminals at frog neuromuscular junctions. For terminals fixed at rest, the contact area between the VM of docked vesicles and PM varied >10-fold with a normal distribution. There was no merging of the membranes. For terminals fixed during repetitive evoked synaptic transmission, the normal distribution of contact areas was shifted to the left, due in part to a decreased number of large contact areas, and there was a subpopulation of large contact areas where the membranes were hemifused, an intermediate preceding complete fusion. Thus, fusion probability of a docked vesicle is related to the extent of its VM-PM contact area. For terminals fixed 1 h after activity, the distribution of contact areas recovered to that at rest, indicating the extent of a VM-PM contact area is dynamic and in equilibrium. The extent of VM-PM contact areas in resting terminals correlated with eccentricity in vesicle shape caused by force toward the PM and with shortness of active zone material macromolecules linking vesicles to PM components, some thought to include Ca 2+ channels. We propose that priming is a variable continuum of events imposing variable fusion probability on each vesicle and is regulated by force-generating shortening of active zone material macromolecules in dynamic equilibrium.synapse | hemifusion | priming | active zone material | electron tomography S ynaptic vesicles (SVs) move toward and dock on (are held in contact with) the presynaptic plasma membrane (PM) of a neuron's axon terminal before fusing with the PM and releasing their neurotransmitter into the synaptic cleft to mediate synaptic transmission (1, 2). Docking is achieved by force-generating interactions of the vesicle membrane (VM) protein synaptobrevin with the PM proteins syntaxin and SNAP25 (3, 4). These interactions, which produce force by forming a coiled coil called the SNARE core complex, are regulated by auxiliary proteins (1, 5-7). Such force on the VM-PM contact site may also play a role in their fusion (8). At typical synapses, docking and fusion take place at structurally specialized regions along the PM called active zones (9, 10). Several lines of evidence suggest that the formation of the SNARE core complex occurs in the macromolecules composing the common active zone organelle, active zone material (AZM) (2,(11)(12)(13)(14), which is positioned near Ca 2+ channels concentrated in the PM at active zones (15-17). Influx of Ca 2+ through the channels after the arrival of a nerve impulse triggers fusion of the VM of docked SVs with the PM.Priming is a step in synaptic transmission between the docking of an SV on, and fusion with, the PM and accounts for the observation that relatively few docked SVs fuse with the PM...

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Section: Discussionmentioning

confidence: 85%

Variable priming of a docked synaptic vesicle

Jung

Szule

Marshall

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

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“…Members of the Synapsin family of phosphoproteins were initially implicated; however, the persistence of connectors in Synapsin triple-knockout mice suggests that other molecules are involved (Hirokawa et al, 1989; Siksou et al, 2007). Diverse molecules have been shown to regulate the distribution of synaptic vesicles, including cytomatrix proteins and the vesicular SNARE protein Synaptobrevin, and are therefore compelling candidates (Fernández-Busnadiego et al, 2010; 2013; Ackermann et al, 2015). …”

Section: Resultsmentioning

confidence: 99%

Three-dimensional imaging of Drosophila motor synapses reveals ultrastructural organizational patterns

Zhan

Bruckner

Zhang

et al. 2016

Journal of Neurogenetics

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We combined cryopreservation of intact Drosophila larvae and electron tomography with comprehensive segmentation of key features to reconstruct the complete ultrastructure of a model glutamatergic synapse in vivo. Presynaptically, we detail a complex network of filaments that connects and organizes synaptic vesicles. We link the complexity of this synaptic vesicle network to proximity to the active zone cytomatrix, consistent with the model that these protein structures function together to regulate synaptic vesicle pools. We identify a net-shaped network of electron-dense filaments spanning the synaptic cleft that suggests conserved organization of transsynaptic adhesion complexes at excitatory synapses. Postsynaptically, we characterize a regular pattern of macromolecules that yields structural insights into the scaffolding of neurotransmitter receptors. Together, these analyses extend our understanding of the ultrastructural correlates of the molecular machines that regulate synaptic communication and reveal an unexpected level of conservation in the nanoscale organization of diverse glutamatergic synapses.

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“…Active zones (AZ) are specialized regions of the presynaptic plasma membrane of neurons designed to regulate the activity-dependent release of neurotransmitter [1]. AZ proteins are thought to function in concert with trans-synaptic cell-adhesion molecules (CAMs) to define sites of neurotransmitter release, holding them in register with the postsynaptic density (PSD) [1, 2].…”

Section: Introductionmentioning

confidence: 99%

“…AZ proteins are thought to function in concert with trans-synaptic cell-adhesion molecules (CAMs) to define sites of neurotransmitter release, holding them in register with the postsynaptic density (PSD) [1, 2]. In addition, they are thought to precisely coordinate aspects of the synaptic vesicle (SV) cycle [3] such as the translocation of SVs from the reserve to the readily releasable pool, and SV exocytosis/endocytosis [1]. …”

Section: Introductionmentioning

confidence: 99%

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Trio, a Rho Family GEF, Interacts with the Presynaptic Active Zone Proteins Piccolo and Bassoon

et al. 2016

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Synaptic vesicles (SVs) fuse with the plasma membrane at a precise location called the presynaptic active zone (AZ). This fusion is coordinated by proteins embedded within a cytoskeletal matrix assembled at the AZ (CAZ). In the present study, we have identified a novel binding partner for the CAZ proteins Piccolo and Bassoon. This interacting protein, Trio, is a member of the Dbl family of guanine nucleotide exchange factors (GEFs) known to regulate the dynamic assembly of actin and growth factor dependent axon guidance and synaptic growth. Trio was found to interact with the C-terminal PBH 9/10 domains of Piccolo and Bassoon via its own N-terminal Spectrin repeats, a domain that is also critical for its localization to the CAZ. Moreover, our data suggest that regions within the C-terminus of Trio negatively regulate its interactions with Piccolo/Bassoon. These findings provide a mechanism for the presynaptic targeting of Trio and support a model in which Piccolo and Bassoon play a role in regulating neurotransmission through interactions with proteins, including Trio, that modulate the dynamic assembly of F-actin during cycles of synaptic vesicle exo- and endocytosis.

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Presynaptic active zones in invertebrates and vertebrates

Cited by 121 publications

References 157 publications

Variable priming of a docked synaptic vesicle

Variable priming of a docked synaptic vesicle

Three-dimensional imaging of Drosophila motor synapses reveals ultrastructural organizational patterns

Trio, a Rho Family GEF, Interacts with the Presynaptic Active Zone Proteins Piccolo and Bassoon

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