Molecular mechanisms governing Ca2+ regulation of evoked and spontaneous release

Schneggenburger, Ralf; Rosenmund, Christian

doi:10.1038/nn.4044

Cited by 89 publications

(103 citation statements)

References 133 publications

(154 reference statements)

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“…In the absence of Cplx3, vesicles undergoing the priming process are lost to unregulated (spontaneous and/or asynchronous) exocytosis driven by global [Ca 2+ ] I . Notably, the “unclamping” of both Ca 2+ -dependent spontaneous and asynchronous release at Cplx3 −/− synapses adds to mounting evidence that these two release modes draw on a common vesicle pool that may be molecularly distinct from the RRP (Kaeser and Regehr, 2014; Kavalali, 2015; Schneggenburger and Rosenmund, 2015). …”

Section: Discussionmentioning

confidence: 99%

“…A key component of this process is the coupling between presynaptic Ca 2+ influx and exocytosis (Kaeser and Regehr, 2014; Kavalali, 2015; Rizo and Xu, 2015; Schneggenburger and Rosenmund, 2015). Several proteins alter the Ca 2+ sensitivity of exocytosis and allow one nerve terminal to sustain multiple modes of transmission, i.e., spontaneous (independent from Ca channel opening), phasic (time locked to presynaptic Ca 2+ influx), and asynchronous (driven by residual [Ca 2+ ] I after closure of Ca channels) (Kaeser and Regehr, 2014; Kavalali, 2015; Schneggenburger and Rosenmund, 2015). …”

Section: Introductionmentioning

confidence: 99%

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Complexin 3 Increases the Fidelity of Signaling in a Retinal Circuit by Regulating Exocytosis at Ribbon Synapses

Mortensen¹,

Park²,

Ke³

et al. 2016

Cell Reports

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SUMMARYComplexin (Cplx) proteins modulate the core SNARE complex to regulate exocytosis. To understand the contributions of Cplx to signaling in a well-characterized neural circuit, we investigated how Cplx3, a retina-specific paralog, shapes transmission at rod bipolar (RB) → AII amacrine cell synapses in the mouse retina. Knockout of Cplx3 strongly attenuated fast, phasic Ca2+-dependent transmission, dependent on local [Ca2+] nanodomains, but enhanced slower Ca2+-dependent transmission, dependent on global intraterminal [Ca2+] ([Ca2+]I). Surprisingly, coordinated multivesicular release persisted at Cplx3−/− synapses, although its onset was slowed. Light-dependent signaling at Cplx3−/− RB → AII synapses was sluggish, owing largely to increased asynchronous release at light offset. Consequently, propagation of RB output to retinal ganglion cells was suppressed dramatically. Our study links Cplx3 expression with synapse and circuit function in a specific retinal pathway and reveals a role for asynchronous release in circuit gain control.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Complexin 3 Increases the Fidelity of Signaling in a Retinal Circuit by Regulating Exocytosis at Ribbon Synapses

Mortensen¹,

Park²,

Ke³

et al. 2016

Cell Reports

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“…Neurotransmitter release from synapses is the predominant mechanism for information transfer between neurons193132. By having a significant impact on synaptic release from synapses targeting EC layer III neurons, pre-synaptic HCN1 channels are likely to play a significant role in modulating synaptic strength and synaptic plasticity and thereby information storage in these neurons.…”

Section: Discussionmentioning

confidence: 99%

HCN1 channels reduce the rate of exocytosis from a subset of cortical synaptic terminals

Huang

Aguado

et al. 2017

Sci Rep

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The hyperpolarization-activated cyclic nucleotide-gated (HCN1) channels are predominantly located in pyramidal cell dendrites within the cortex. Recent evidence suggests these channels also exist pre-synaptically in a subset of synaptic terminals within the mature entorhinal cortex (EC). Inhibition of pre-synaptic HCN channels enhances miniature excitatory post-synaptic currents (mEPSCs) onto EC layer III pyramidal neurons, suggesting that these channels decrease the release of the neurotransmitter, glutamate. Thus, do pre-synaptic HCN channels alter the rate of synaptic vesicle exocytosis and thereby enhance neurotransmitter release? To address this, we imaged the release of FM1-43, a dye that is incorporated into synaptic vesicles, from EC synaptic terminals using two photon microscopy in slices obtained from forebrain specific HCN1 deficient mice, global HCN1 knockouts and their wildtype littermates. This coupled with electrophysiology and pharmacology showed that HCN1 channels restrict the rate of exocytosis from a subset of cortical synaptic terminals within the EC and in this way, constrain non-action potential-dependent and action potential-dependent spontaneous release as well as synchronous, evoked release. Since HCN1 channels also affect post-synaptic potential kinetics and integration, our results indicate that there are diverse ways by which HCN1 channels influence synaptic strength and plasticity.

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“…119 In the presynaptic active zone, the relatively low calcium sensitivity of the vesicular calcium sensor proteins demands a very close alignment of calcium channels and releasable vesicles within a radius below 100 nm. 20,46,71,118 Investigations of the release probability, channel distribution, as well as evoked calcium signals, point to a clustered distribution of presynaptic calcium channels. 4,66,103 The distance of VGCC clusters and synaptic vesicles varies between different synapses 7,46,71,135 and implies different channel arrangements in the different synapses.…”

Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

Surface dynamics of voltage-gated ion channels

et al. 2016

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Neurons encode information in fast changes of the membrane potential, and thus electrical membrane properties are critically important for the integration and processing of synaptic inputs by a neuron. These electrical properties are largely determined by ion channels embedded in the membrane. The distribution of most ion channels in the membrane is not spatially uniform: they undergo activity-driven changes in the range of minutes to days. Even in the range of milliseconds, the composition and topology of ion channels are not static but engage in highly dynamic processes including stochastic or activity-dependent transient association of the pore-forming and auxiliary subunits, lateral diffusion, as well as clustering of different channels. In this review we briefly discuss the potential impact of mobile sodium, calcium and potassium ion channels and the functional significance of this for individual neurons and neuronal networks.

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Molecular mechanisms governing Ca2+ regulation of evoked and spontaneous release

Cited by 89 publications

References 133 publications

Complexin 3 Increases the Fidelity of Signaling in a Retinal Circuit by Regulating Exocytosis at Ribbon Synapses

Complexin 3 Increases the Fidelity of Signaling in a Retinal Circuit by Regulating Exocytosis at Ribbon Synapses

HCN1 channels reduce the rate of exocytosis from a subset of cortical synaptic terminals

Surface dynamics of voltage-gated ion channels

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