RIM-Binding Protein Links Synaptic Homeostasis to the Stabilization and Replenishment of High Release Probability Vesicles

Müller, Martin; Genç, Özgür; Davis, Graeme W.

doi:10.1016/j.neuron.2015.01.024

Cited by 93 publications

(144 citation statements)

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“…An independent study made a similar observation, showing that reduced Ca V 2.1 channel abundance and a correlated ~50% decrease in single action potential (AP) induced calcium influx, did not impair the rapid induction of presynaptic homeostasis (Gavino et al, 2015). Third, synaptic homeostasis is fully expressed over a 50-fold range of extracelluar calcium concentration (0.3 to 15mM [Ca 2+ ] e ) (Muller et al, 2015), arguing that the absolute amount of calcium influx per action potential does not influence the homeostatic modulation of presynaptic neurotransmitter release. Here, we confirm this finding in the α2δ-3 mutant background.…”

Section: Resultsmentioning

confidence: 99%

α2δ-3 Is Required for Rapid Transsynaptic Homeostatic Signaling

et al. 2016

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The homeostatic modulation of neurotransmitter release, termed presynaptic homeostatic potentiation (PHP), is a fundamental type of neuromodulation, conserved from Drosophila to human, that stabilizes information transfer at synaptic connections throughout the nervous system. Here we demonstrate that α2δ-3, an auxiliary subunit of the presynaptic calcium channel, is required for PHP. The α2δ gene family has been linked to chronic pain, epilepsy, autism and the action of two psychiatric drugs, gabapentin and pregabalin. We demonstrate that loss of α2δ-3 blocks both the rapid induction and sustained expression of PHP due to a failure to potentiate presynaptic calcium influx and the RIM-dependent readily-releasable vesicle pool. These deficits are independent of α2δ-3-mediated regulation of baseline calcium influx and presynaptic action potential waveform. α2δ proteins reside at the extracellular face of presynaptic release sites throughout the nervous system, an ideal site to mediate rapid, trans-synaptic homeostatic signaling in health and disease.

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Section: Resultsmentioning

confidence: 99%

α2δ-3 Is Required for Rapid Transsynaptic Homeostatic Signaling

et al. 2016

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“…Recently, Acuna et al (8) showed that deletion of RIM-BP1 and RIM-BP2 in the murine Calyx of Held impairs the reliability of evoked neurotransmitter release, presumably due to an uncoupling of Ca V s from release sites. At the Drosophila NMJ, the RIM-BP ortholog DRBP, together with Bruchpilot, is an AZ core component, and elimination of DRBP causes severe structural deficits in AZ organization, associated with strongly impaired basal transmission and STP (6,7).…”

Section: Discussionmentioning

confidence: 99%

“…The Drosophila homolog of RIM-binding proteins (DRBP) is indeed crucial for neurotransmitter release at the AZ of neuromuscular junctions (NMJs) because loss of DRBP reduces Ca V abundance and impairs the integrity of the AZ scaffold (6). DRBP-deficient flies show severe impairment of neurotransmitter release along with increased short-term facilitation (6,7).…”

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confidence: 99%

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses

Grauel

Maglione

Reddy-Alla

et al. 2016

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

102

178

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The tight spatial coupling of synaptic vesicles and voltage-gated Ca 2+ channels (Ca V s) ensures efficient action potential-triggered neurotransmitter release from presynaptic active zones (AZs). Rab-interacting molecule-binding proteins (RIM-BPs) interact with Ca 2+ channels and via RIM with other components of the release machinery. Although human RIM-BPs have been implicated in autism spectrum disorders, little is known about the role of mammalian RIM-BPs in synaptic transmission. We investigated RIM-BP2-deficient murine hippocampal neurons in cultures and slices. Short-term facilitation is significantly enhanced in both model systems. Detailed analysis in culture revealed a reduction in initial release probability, which presumably underlies the increased shortterm facilitation. Superresolution microscopy revealed an impairment in Ca V 2.1 clustering at AZs, which likely alters Ca 2+ nanodomains at release sites and thereby affects release probability. Additional deletion of RIM-BP1 does not exacerbate the phenotype, indicating that RIM-BP2 is the dominating RIM-BP isoform at these synapses.RIM-BP2 | calcium channel coupling | release probability | short-term plasticity | active zone structure A t the presynapse, coupling between action potentials (APs) and synaptic vesicle fusion is exquisitely precise, ensuring high temporal fidelity of neuron-to-neuron signaling in the nervous system. Two properties are thought to be responsible for this remarkable precision: a highly efficient release apparatus that transduces Ca 2+ signals into vesicle fusion and a tightly organized active zone (AZ), where the release apparatus and voltage-gated Ca 2+ channels (Ca V s) are spatially coupled. Rab-interacting molecules (RIM) are thought to contribute to both properties, because loss of RIM impairs vesicle priming (1) and Ca V localization at the AZ (2). RIM-binding proteins (RIM-BPs) directly interact with RIM (3), the pore-forming subunits of Ca V 1 and Ca V 2 channels (2, 4, 5), and Bassoon (5), and have therefore been suggested to play a role in presynaptic Ca V localization. The Drosophila homolog of RIM-binding proteins (DRBP) is indeed crucial for neurotransmitter release at the AZ of neuromuscular junctions (NMJs) because loss of DRBP reduces Ca V abundance and impairs the integrity of the AZ scaffold (6). DRBP-deficient flies show severe impairment of neurotransmitter release along with increased short-term facilitation (6, 7).Recently, Acuna et al. (8) published a report on the combined loss of RIM-BP1 and RIM-BP2 in mouse synapses. The authors report that although RIM-BPs are not essential for synaptic transmission, AP-triggered neurotransmitter release is more variable and the sensitivity to the Ca 2+ chelator EGTA is increased at the Calyx of Held, suggesting a larger coupling distance of Ca V and the release machinery.In the present study, we further investigated the consequences of constitutive deletion of RIM-BP2 on the structure and function of mouse hippocampal synapses. We show that loss of RIM-BP2 lead...

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“…There appear to be a core set of genes necessary for both acute and chronic PHP expression, including ones involved in the homeostatic modulation of synaptic vesicle trafficking, presynaptic excitability, calcium channel activity, and active zone remodeling (Dickman and Davis, 2009; Frank et al, 2006; Muller et al, 2015; Younger et al, 2013). However, other genes appear to be dispensable for this core program, and may rather be involved in secondary functions, such as maintaining PHP expression over chronic time scales or supporting other aspects of homeostatic adaptation (Frank et al, 2009; Penney et al, 2012; Penney et al, 2016; Spring et al, 2016; Tsurudome et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Disparate Postsynaptic Induction Mechanisms Ultimately Converge to Drive the Retrograde Enhancement of Presynaptic Efficacy

2017

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SUMMARY Retrograde signaling systems are fundamental modes of communication that synapses utilize to dynamically and adaptively modulate activity. However, the inductive mechanisms that gate retrograde communication in the postsynaptic compartment remain enigmatic. We have investigated retrograde signaling at the Drosophila neuromuscular junction, where three seemingly disparate perturbations to the postsynaptic cell trigger a similar enhancement in presynaptic neurotransmitter release. We show that the same presynaptic genetic machinery and enhancements in active zone structure are utilized by each inductive pathway. However, all three induction mechanisms differ in temporal, translational, and CamKII activity requirements to initiate retrograde signaling in the postsynaptic cell. Intriguingly, pharmacological blockade of postsynaptic glutamate receptors, and not calcium influx through these receptors, is necessary and sufficient to induce rapid retrograde homeostatic signaling through CamKII. Thus, three distinct induction mechanisms converge on the same retrograde signaling system to drive the homeostatic strengthening of presynaptic neurotransmitter release.

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RIM-Binding Protein Links Synaptic Homeostasis to the Stabilization and Replenishment of High Release Probability Vesicles

Cited by 93 publications

References 36 publications

α2δ-3 Is Required for Rapid Transsynaptic Homeostatic Signaling

α2δ-3 Is Required for Rapid Transsynaptic Homeostatic Signaling

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses

Disparate Postsynaptic Induction Mechanisms Ultimately Converge to Drive the Retrograde Enhancement of Presynaptic Efficacy

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