Spontaneous and Evoked Release Are Independently Regulated at Individual Active Zones

Melom, Jan E; Akbergenova, Yulia; Gavornik, Jeffrey P.; Littleton, J Troy

doi:10.1523/jneurosci.3334-13.2013

Cited by 181 publications

(228 citation statements)

References 35 publications

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“…However, this does not fit with the observed decrease in size and intensity of Brp positive puncta in these mutants. Active zones with low or nonfunctional Brp are known to be more strongly associated with increased spontaneous neurotransmission (Melom et al 2013;Peled et al 2014). Considering the involvement of postsynaptic signaling in initiating satellite bouton formation, we think altered neurotransmission possibly together with impaired postsynaptic or retrograde signaling, contributes to the altered synaptic morphology in Dmon1 mutants.…”

Section: Discussionmentioning

confidence: 92%

A Presynaptic Regulatory System Acts Transsynaptically via Mon1 to Regulate Glutamate Receptor Levels in Drosophila

et al. 2015

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Mon1 is an evolutionarily conserved protein involved in the conversion of Rab5 positive early endosomes to late endosomes through the recruitment of Rab7. We have identified a role for Drosophila Mon1 in regulating glutamate receptor levels at the larval neuromuscular junction. We generated mutants in Dmon1 through P-element excision. These mutants are short-lived with strong motor defects. At the synapse, the mutants show altered bouton morphology with several small supernumerary or satellite boutons surrounding a mature bouton; a significant increase in expression of GluRIIA and reduced expression of Bruchpilot. Neuronal knockdown of Dmon1 is sufficient to increase GluRIIA levels, suggesting its involvement in a presynaptic mechanism that regulates postsynaptic receptor levels. Ultrastructural analysis of mutant synapses reveals significantly smaller synaptic vesicles. Overexpression of vglut suppresses the defects in synaptic morphology and also downregulates GluRIIA levels in Dmon1 mutants, suggesting that homeostatic mechanisms are not affected in these mutants. We propose that DMon1 is part of a presynaptically regulated transsynaptic mechanism that regulates GluRIIA levels at the larval neuromuscular junction.

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Section: Discussionmentioning

confidence: 92%

A Presynaptic Regulatory System Acts Transsynaptically via Mon1 to Regulate Glutamate Receptor Levels in Drosophila

et al. 2015

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“…What mechanism is ultimately used to separate Cpx's role in spontaneous vs. evoked release is still unclear, and may involve a complex interplay with the SNARE complex and other SNARE-associated proteins, including Syt (37,38). These distinct roles may also be manifest through effects of Cpx on molecularly distinct pools of vesicles (39), or on specific active zones dedicated to evoked vs. spontaneous release (40). Given that Cpx mutants that interrupt the trans Cpx/SNARE array support evoked release, it is unlikely that a Cpx-mediated cross-linking of SNARE complexes is required during Ca 2+ -triggered release.…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis of the Complexin trans-clamping model for cross-linking SNARE complexes in vivo

Cho

Kümmel

et al. 2014

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

102

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Complexin (Cpx) is a SNARE-binding protein that regulates neurotransmission by clamping spontaneous synaptic vesicle fusion in the absence of Ca 2+ influx while promoting evoked release in response to an action potential. Previous studies indicated Cpx may cross-link multiple SNARE complexes via a trans interaction to function as a fusion clamp. During Ca 2+ influx, Cpx is predicted to undergo a conformational switch and collapse onto a single SNARE complex in a cis-binding mode to activate vesicle release. To test this model in vivo, we performed structure-function studies of the Cpx protein in Drosophila. Using genetic rescue approaches with cpx mutants that disrupt SNARE cross-linking, we find that manipulations that are predicted to block formation of the trans SNARE array disrupt the clamping function of Cpx. Unexpectedly, these same mutants rescue action potential-triggered release, indicating trans-SNARE cross-linking by Cpx is not a prerequisite for triggering evoked fusion. In contrast, mutations that impair Cpxmediated cis-SNARE interactions that are necessary for transition from an open to closed conformation fail to rescue evoked release defects in cpx mutants, although they clamp spontaneous release normally. Our in vivo genetic manipulations support several predictions made by the Cpx cross-linking model, but unexpected results suggest additional mechanisms are likely to exist that regulate Cpx's effects on SNARE-mediated fusion. Our findings also indicate that the inhibitory and activating functions of Cpx are genetically separable, and can be mapped to distinct molecular mechanisms that differentially regulate the SNARE fusion machinery.synapse | neurotransmitter release | exocytosis

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“…Each AZ is spatially separated and opposed by a distinct cluster of ionotropic GluRs. The tight coupling of release sites and clustered receptors allows imaging of single SV fusion events at individual release sites by measuring Ca 2+ influx through postsynaptic GluRs following neurotransmitter release (Desai and Lnenicka 2011;Peled and Isacoff 2011;Melom et al 2013;Peled et al 2014). This allows the generation of release probability maps for individual release sites (Figure 3), a technique that has not been achieved at synaptic connections in other model systems.…”

Section: Synaptic Vesicle Recycling and Recoverymentioning

confidence: 99%

“…AZs are readily identifiable by electron microscopy (EM) as electron-dense T-bar structures (Feeney et al 1998) (Figure 1A). The precise matching of AZ to GluR cluster has allowed optical imaging of synaptic vesicle (SV) release at individual release sites at the fly NMJ (Peled and Isacoff 2011;Melom et al 2013), yielding an experimental system that offers unprecedented tools for analyzing how synaptic transmission is organized and regulated at individual AZs.…”

Section: Introduction 345mentioning

confidence: 99%

Transmission, Development, and Plasticity of Synapses

Harris¹,

2015

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Chemical synapses are sites of contact and information transfer between a neuron and its partner cell. Each synapse is a specialized junction, where the presynaptic cell assembles machinery for the release of neurotransmitter, and the postsynaptic cell assembles components to receive and integrate this signal. Synapses also exhibit plasticity, during which synaptic function and/or structure are modified in response to activity. With a robust panel of genetic, imaging, and electrophysiology approaches, and strong evolutionary conservation of molecular components, Drosophila has emerged as an essential model system for investigating the mechanisms underlying synaptic assembly, function, and plasticity. We will discuss techniques for studying synapses in Drosophila, with a focus on the larval neuromuscular junction (NMJ), a well-established model glutamatergic synapse. Vesicle fusion, which underlies synaptic release of neurotransmitters, has been well characterized at this synapse. In addition, studies of synaptic assembly and organization of active zones and postsynaptic densities have revealed pathways that coordinate those events across the synaptic cleft. We will also review modes of synaptic growth and plasticity at the fly NMJ, and discuss how pre-and postsynaptic cells communicate to regulate plasticity in response to activity. KEYWORDS FlyBook; Drosophila; synapse; neurotransmitter release; synaptic plasticity; active zone; synaptic vesicle TABLE OF CONTENTS Abstract 345Introduction 345

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Spontaneous and Evoked Release Are Independently Regulated at Individual Active Zones

Cited by 181 publications

References 35 publications

A Presynaptic Regulatory System Acts Transsynaptically via Mon1 to Regulate Glutamate Receptor Levels in Drosophila

A Presynaptic Regulatory System Acts Transsynaptically via Mon1 to Regulate Glutamate Receptor Levels in Drosophila

Genetic analysis of the Complexin trans-clamping model for cross-linking SNARE complexes in vivo

Transmission, Development, and Plasticity of Synapses

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