RIM-BP2 primes synaptic vesicles via recruitment of Munc13-1 at hippocampal mossy fiber synapses

Brockmann, Marisa M; Maglione, Marta; Willmes, Claudia; Stumpf, Alexander; Bouazza, Boris A; Moreno-Velasquez, Laura; Grauel, M. Katharina; Beed, Prateep; Lehmann, Martin; Gimber, Niclas; Schmoranzer, Jan; Sigrist, Stephan J.; Rosenmund, Christian; Schmitz, Dietmar

doi:10.7554/elife.43243

Cited by 57 publications

(48 citation statements)

References 41 publications

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“…We tested this hypothesis and performed gSTED microscopy to measure the distance between Cav2.1 and Munc13-1 signals. We confirmed a rather loose coupling distance of about 60 nm between calcium source and release sites at mossy fibers, as previously estimated by electrophysiological recordings (Vyleta and Jonas, 2014) and STED microscopy (Brockmann et al, 2019). These values were similar for control and potentiated synapses, suggesting that the tightening of the distance between calcium source and release sites does not underlie presynaptic potentiation.…”

Section: Discussionsupporting

confidence: 89%

“…95% of distances were shorter than 100 nm ( Figure 3C, D). The measured mean distance is consistent with the loose coupling configuration of hMFBs previously determined by electrophysiological recordings (Vyleta and Jonas, 2014), as well as by a previous study measuring the coupling distance by two-color gSTED (Brockmann et al, 2019). Similar measurements in the stratum radiatum of the CA1 region gave a similar average distance between Cav2.1 and Munc13-1 clusters as the one observed in CA3 control synapses (Table S2, p = 0.53, Mann Mann-Whitney-test).…”

Section: No Change In Coupling Distance At Potentiated Synapsessupporting

confidence: 89%

“…gSTED allowed us to detect punctate immunostaining of synaptic proteins. Here, we refer to puncta as clusters, as in a previous study (Brockmann et al, 2019). We measured the distance between presynaptic Cav2.1 and Munc13-1 clusters only when they were juxtaposed to a Homer cluster, making sure that the clusters belonged to the same AZ ( Figure 3B).…”

Section: No Change In Coupling Distance At Potentiated Synapsesmentioning

confidence: 99%

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Increased and synchronous recruitment of release sites underlies hippocampal mossy fiber presynaptic potentiation

Orlando

Dvorzhak

Bruentgens

et al. 2020

Preprint

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Synaptic plasticity is a cellular model for learning and memory. However, the expression mechanisms underlying presynaptic forms of plasticity are not well understood. Here, we investigate functional and structural correlates of long-term potentiation at large hippocampal mossy fiber boutons induced by the adenylyl cyclase activator forskolin. We performed two-photon imaging of the genetically encoded glutamate sensor iGlu u that revealed an increase in the surface area used for glutamate release at potentiated terminals. Moreover, time-gated stimulated emission depletion microscopy revealed no change in the coupling distance between immunofluorescence signals from calcium channels and release sites. Finally, by high-pressure freezing and transmission electron microscopy analysis, we found a fast remodeling of synaptic ultrastructure at potentiated boutons : synaptic vesicles dispersed in the terminal and accumulated at the active zones, while active zone density and synaptic complexity increased. We suggest that these rapid and early structural rearrangements likely enable long-term increase in synaptic strength.

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Section: Discussionsupporting

confidence: 89%

Section: No Change In Coupling Distance At Potentiated Synapsessupporting

confidence: 89%

Section: No Change In Coupling Distance At Potentiated Synapsesmentioning

confidence: 99%

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Increased and synchronous recruitment of release sites underlies hippocampal mossy fiber presynaptic potentiation

Orlando

Dvorzhak

Bruentgens

et al. 2020

Preprint

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“…The synapse-type-specific AZ protein composition is also evident in other vertebrate synapses. For example, in hippocampus mossy fiber synapses, RIM expression is low, and Munc13-1 uses RIM-BP to prime SVs ( Brockmann et al, 2019 ). Overall, it is noteworthy that some synapses are prone to use more than one mode of priming.…”

Section: Discussionmentioning

confidence: 99%

Disentangling the Roles of RIM and Munc13 in Synaptic Vesicle Localization and Neurotransmission

et al. 2020

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Efficient neurotransmitter release at the presynaptic terminal requires docking of synaptic vesicles to the active zone membrane and formation of fusion-competent synaptic vesicles near voltage-gated Ca 2+ channels. Rab3-interacting molecule (RIM) is a critical active zone organizer, as it recruits Ca 2+ channels and activates synaptic vesicle docking and priming via Munc13-1. However, our knowledge about Munc13-independent contributions of RIM to active zone functions is limited. To identify the functions that are solely mediated by RIM, we used genetic manipulations to control RIM and Munc13-1 activity in cultured hippocampal neurons from mice of either sex and compared synaptic ultrastructure and neurotransmission. We found that RIM modulates synaptic vesicle localization in the proximity of the active zone membrane independent of Munc13-1. In another step, both RIM and Munc13 mediate synaptic vesicle docking and priming. In addition, while the activity of both RIM and Munc13-1 is required for Ca 2+ -evoked release, RIM uniquely controls neurotransmitter release efficiency. However, activity-dependent augmentation of synaptic vesicle pool size relies exclusively on the action of Munc13s. Based on our results, we extend previous findings and propose a refined model in which RIM and Munc13-1 act in overlapping and independent stages of synaptic vesicle localization and release. SIGNIFICANCE STATEMENT The presynaptic active zone is composed of scaffolding proteins that functionally interact to localize synaptic vesicles to release sites, ensuring neurotransmission. Our current knowledge of the presynaptic active zone function relies on structure-function analysis, which has provided detailed information on the network of interactions and the impact of active zone proteins. Yet, the hierarchical, redundant, or independent cooperation of each active zone protein to synapse functions is not fully understood. Rab3-interacting molecule and Munc13 are the two key functionally interacting active zone proteins. Here, we dissected the distinct actions of Rab3-interacting molecule and Munc13-1 from both ultrastructural and physiological aspects. Our findings provide a more detailed view of how these two presynaptic proteins orchestrate their functions to achieve synaptic transmission.

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“…RIM-BP family proteins with the C-terminal SH3-II/III domains bind to Ca 2+ channels ( Hibino et al, 2002 ; Liu et al, 2011 ), release factor Unc13A ( Böhme et al, 2016 ), and RIM, another critical AZ scaffold protein. At Drosophila neuromuscular junction (NMJ) synapses, rim-bp null alleles provoke a most severe functional phenotype ( Liu et al, 2011 ), stronger than for rim and rim-bp single mutants at most mammalian synapses ( Andrews-Zwilling et al, 2006 ; Betz et al, 2001 ; Brockmann et al, 2019 ). Here we exploit the severity of the synaptic Drosophila rim-bp phenotype for a detailed structure-function analysis at Drosophila larval neuromuscular (NMJ) synapses.…”

Section: Introductionmentioning

confidence: 99%

RIM-binding protein couples synaptic vesicle recruitment to release sites

Petzoldt

Götz

Driller

et al. 2020

Journal of Cell Biology

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At presynaptic active zones, arrays of large conserved scaffold proteins mediate fast and temporally precise release of synaptic vesicles (SVs). SV release sites could be identified by clusters of Munc13, which allow SVs to dock in defined nanoscale relation to Ca2+ channels. We here show in Drosophila that RIM-binding protein (RIM-BP) connects release sites physically and functionally to the ELKS family Bruchpilot (BRP)-based scaffold engaged in SV recruitment. The RIM-BP N-terminal domain, while dispensable for SV release site organization, was crucial for proper nanoscale patterning of the BRP scaffold and needed for SV recruitment of SVs under strong stimulation. Structural analysis further showed that the RIM-BP fibronectin domains form a “hinge” in the protein center, while the C-terminal SH3 domain tandem binds RIM, Munc13, and Ca2+ channels release machinery collectively. RIM-BPs’ conserved domain architecture seemingly provides a relay to guide SVs from membrane far scaffolds into membrane close release sites.

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RIM-BP2 primes synaptic vesicles via recruitment of Munc13-1 at hippocampal mossy fiber synapses

Cited by 57 publications

References 41 publications

Increased and synchronous recruitment of release sites underlies hippocampal mossy fiber presynaptic potentiation

Increased and synchronous recruitment of release sites underlies hippocampal mossy fiber presynaptic potentiation

Disentangling the Roles of RIM and Munc13 in Synaptic Vesicle Localization and Neurotransmission

RIM-binding protein couples synaptic vesicle recruitment to release sites

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