Munc13-3 Superprimes Synaptic Vesicles at Granule Cell-to-Basket Cell Synapses in the Mouse Cerebellum

Ishiyama, Shimpei; Schmidt, Hartmut; Cooper, Benjamin H.; Eilers, Jens

doi:10.1523/jneurosci.2060-14.2014

Cited by 38 publications

(48 citation statements)

References 51 publications

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“…Munc13-3 is strongly expressed in PF varicosities (PF v s). Notably, its expression is upregulated during development (Augustin et al, 1999), and Munc13-3-deficient synapses have decreased p r (Augustin et al, 2001;Ishiyama et al, 2014). These findings would be consistent with a role of Munc13-3 in regulating AZ topography and coupling distances during development.…”

Section: Introductionsupporting

confidence: 75%

“…than in tight coupling regimes (Adler et al, 1991). Previously, we found that loading of PF v with membrane-permeable EGTA (EGTA-AM) significantly affects release from young (postnatal day [P] 8-10) but not from matured (P21-P24) PF terminals onto PNs in the WT (Baur et al, 2015) and that EGTA-AM affects release at mature PF to basket cell (BC) synapses in Munc13-3 À/À but not in WT mice (Ishiyama et al, 2014). These data would be compatible with a critical role of Munc13-3 in the maturation of the release process.…”

Section: Impaired Developmental Tightening Of Coupling In Munc13-3 à/àmentioning

confidence: 99%

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Munc13-3 Is Required for the Developmental Localization of Ca2+ Channels to Active Zones and the Nanopositioning of Cav2.1 Near Release Sensors

et al. 2018

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Spatial relationships between Ca channels and release sensors at active zones (AZs) are a major determinant of synaptic fidelity. They are regulated developmentally, but the underlying molecular mechanisms are largely unclear. Here, we show that Munc13-3 regulates the density of Ca2.1 and Ca2.2 channels, alters the localization of Ca2.1, and is required for the development of tight, nanodomain coupling at parallel-fiber AZs. We combined EGTA application and Ca-channel pharmacology in electrophysiological and two-photon Ca imaging experiments with quantitative freeze-fracture immunoelectron microscopy and mathematical modeling. We found that a normally occurring developmental shift from release being dominated by Ca influx through Ca2.1 and Ca2.2 channels with domain overlap and loose coupling (microdomains) to a nanodomain Ca2.1 to sensor coupling is impaired in Munc13-3-deficient synapses. Thus, at AZs lacking Munc13-3, release remained triggered by Ca2.1 and Ca2.2 microdomains, suggesting a critical role of Munc13-3 in the formation of release sites with calcium channel nanodomains.

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Section: Introductionsupporting

confidence: 75%

Section: Impaired Developmental Tightening Of Coupling In Munc13-3 à/àmentioning

confidence: 99%

Munc13-3 Is Required for the Developmental Localization of Ca2+ Channels to Active Zones and the Nanopositioning of Cav2.1 Near Release Sensors

et al. 2018

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“…Furthermore, at parallel fibre to Purkinje cell synapses, Munc13‐3 mediates super‐priming (Ishiyama et al . ), most probably by shortening the coupling distance (Kusch et al . ).…”

Section: Discussionmentioning

confidence: 99%

Apparent calcium dependence of vesicle recruitment

Ritzau-Jost

Jablonski

Viotti

et al. 2018

The Journal of Physiology

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During sustained synaptic transmission, recruitment of new transmitter-filled vesicles to the release site counteracts vesicle depletion and thus synaptic depression. An elevated intracellular Ca concentration has been proposed to accelerate the rate of vesicle recruitment at many synapses. This conclusion is often based on the finding that increased intracellular Ca buffering slows the recovery from synaptic depression. However, the molecular mechanisms of the activity-dependent acceleration of vesicle recruitment have only been analysed at some synapses. Using physiological stimulation patterns in postsynaptic recordings and step depolarizations in presynaptic bouton recordings, we investigate vesicle recruitment at cerebellar mossy fibre boutons. We show that increased intracellular Ca buffering slows recovery from depression dramatically. However, pharmacological and genetic interference with calmodulin or the calmodulin-Munc13 pathway, which has been proposed to mediate Ca -dependence of vesicle recruitment, barely affects vesicle recovery from depression. Furthermore, we show that cerebellar mossy fibre boutons have two pools of vesicles: rapidly fusing vesicles that recover slowly and slowly fusing vesicles that recover rapidly. Finally, models adopting such two pools of vesicles with Ca -independent recruitment rates can explain the slowed recovery from depression upon increased Ca buffering. Our data do not rule out the involvement of the calmodulin-Munc13 pathway during stronger stimuli or other molecular pathways mediating Ca -dependent vesicle recruitment at cerebellar mossy fibre boutons. However, we show that well-established two-pool models predict an apparent Ca -dependence of vesicle recruitment. Thus, previous conclusions of Ca -dependent vesicle recruitment based solely on increased intracellular Ca buffering should be considered with caution.

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“…Using styryl dyes and cultured hippocampal neurons, strong heterogeneity of release was observed among individual boutons, when stimulating at 1 Hz, whereas synaptic strength was more uniform, with some of the remaining heterogeneity disappearing after a few stimuli, when stimulating at 10 Hz (47). Ishiyama et al (65) describe a decrease in p in granule cell to basket cell synapses of the cerebellum of Munc13-3 −/− mice. They interpret their observations as a loss of a superpriming action of Munc13-3.…”

Section: Superpriming May Be a Widely Spread Phenomenon Among Excitatorymentioning

confidence: 99%

Superpriming of synaptic vesicles as a common basis for intersynapse variability and modulation of synaptic strength

Taschenberger

Woehler

Neher

2016

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

110

165

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Glutamatergic synapses show large variations in strength and shortterm plasticity (STP). We show here that synapses displaying an increased strength either after posttetanic potentiation (PTP) or through activation of the phospholipase-C-diacylglycerol pathway share characteristic properties with intrinsically strong synapses, such as (i) pronounced short-term depression (STD) during high-frequency stimulation; (ii) a conversion of that STD into a sequence of facilitation followed by STD after a few conditioning stimuli at low frequency; (iii) an equalizing effect of such conditioning stimulation, which reduces differences among synapses and abolishes potentiation; and (iv) a requirement of long periods of rest for reconstitution of the original STP pattern. These phenomena are quantitatively described by assuming that a small fraction of "superprimed" synaptic vesicles are in a state of elevated release probability (p ∼ 0.5). This fraction is variable in size among synapses (typically about 30%), but increases after application of phorbol ester or during PTP. The majority of vesicles, released during repetitive stimulation, have low release probability (p ∼ 0.1), are relatively uniform in number across synapses, and are rapidly recruited. In contrast, superprimed vesicles need several seconds to be regenerated. They mediate enhanced synaptic strength at the onset of burst-like activity, the impact of which is subject to modulation by slow modulatory transmitter systems.posttetanic potentiation | short-term plasticity | calyx of Held | Munc13 | phorbol ester G lutamatergic synapses display a variety of dynamic changes in response to stimulation with action potential (AP) trains, ranging from immediate short-term depression to facilitation followed by depression (1). Both pharmacological (2-6) and molecular (7-9) perturbations have been described, which change such patterns from one to the other in a given synapse. Short-term plasticity (STP) has been shown to underlie many basic signal processing tasks of circuits in the central nervous system (10-13) and rapid changes of STP have been considered "... to be an almost necessary condition for the existence of (short-lived) activity states in the central nervous system" (ref. 14, p. 247). The balance between facilitation and depression is shifted during posttetanic potentiation (PTP) (15) and behavioral states are dynamically regulated by STP (16). Regulation occurs through slow, modulatory transmitter systems (17, 18). However, many open questions regarding the mechanisms underlying such changes remain. Modulation of presynaptic voltage-gated Ca 2+ channels by slow transmitter systems is probably the most powerful mechanism of changing release probability (p) of synaptic vesicles (SVs) (19)(20)(21). Changes in intrinsic [Ca 2+ ] i sensitivity of the release apparatus also contribute and have been investigated in the context of the phospholipase-C-diacylglycerol (PLC-DAG) signaling pathway (22-26) and posttetanic potentiation (15,(27)(28)(29)(30), but the infl...

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Munc13-3 Superprimes Synaptic Vesicles at Granule Cell-to-Basket Cell Synapses in the Mouse Cerebellum

Cited by 38 publications

References 51 publications

Munc13-3 Is Required for the Developmental Localization of Ca2+ Channels to Active Zones and the Nanopositioning of Cav2.1 Near Release Sensors

Munc13-3 Is Required for the Developmental Localization of Ca2+ Channels to Active Zones and the Nanopositioning of Cav2.1 Near Release Sensors

Apparent calcium dependence of vesicle recruitment

Superpriming of synaptic vesicles as a common basis for intersynapse variability and modulation of synaptic strength

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