Acute destruction of the synaptic ribbon reveals a role for the ribbon in vesicle priming

Snellman, Josefin; Mehta, Bhupesh; Babai, Norbert; Bartoletti, Theodore M.; Akmentin, Wendy; Francis, Adam; Matthews, Gary; Thoreson, Wallace B.; Zenisek, David

doi:10.1038/nn.2870

Cited by 123 publications

(159 citation statements)

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“…Vesicles can be resupplied to the synaptic ribbon through a fast mechanism ( 800 ms) that is regulated by the actions of Ca 2+ / CaM on vesicle attachment sites on the ribbon, several hundred nanometers distant from Ca 2+ entry through channels located at the ribbon base. Vesicles can also attach through a slower, Ca 2+ / CaM-independent process that has a time constant of 13 s. Vesicle priming appears to involve the synaptic ribbon (Snellman et al, 2011). Exocytosis occurs in two phases, with time constants of 6 ms and 170 ms that represent fast fusion of the IRP (blue) and movement of vesicles from the ribbon-associated reserve pool (yellow) to release sites near the ribbon base, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…1). Release from cones appears to occur only at ribbons (Snellman et al, 2011), and this stimulus releases the entire immediately releasable pool (IRP) of vesicles at the base of the ribbon with 100% release probability . Depression at the photoreceptor synapse is mediated principally by depletion of vesicles from the releasable pool rather than by desensitization of postsynaptic AMPA receptors (Rabl et al, 2006).…”

Section: R E S U L T Smentioning

confidence: 99%

“…e d u Abbreviations used in this paper: BC, bipolar cell; CaM, calmodulin; EPSC, excitatory postsynaptic current; ERG, electroretinogram; HC, horizontal cell; IRP, immediately releasable pool; MLCK, myosin light chain kinase; PPR, paired pulse ratio; RBC, rod BC; TIRFM, total internal reflection fluorescence microscopy. primed vesicles for release at the presynaptic membrane (Heidelberger et al, 2005;Snellman et al, 2011). Recent studies have shown that the interplay of vesicle release and replenishment at the ribbon are important in encoding luminance and contrast by cones (Jackman et al, 2009;Babai et al, 2010) and rod BCs (RBCs; Oesch and Diamond, 2011;Ke et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Calmodulin enhances ribbon replenishment and shapes filtering of synaptic transmission by cone photoreceptors

Hook¹,

Parmelee²,

Chen³

et al. 2014

J Cell Biol

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At the first synapse in the vertebrate visual pathway, light-evoked changes in photoreceptor membrane potential alter the rate of glutamate release onto second-order retinal neurons. This process depends on the synaptic ribbon, a specialized structure found at various sensory synapses, to provide a supply of primed vesicles for release. Calcium (Ca 2+ ) accelerates the replenishment of vesicles at cone ribbon synapses, but the mechanisms underlying this acceleration and its functional implications for vision are unknown. We studied vesicle replenishment using paired whole-cell recordings of cones and postsynaptic neurons in tiger salamander retinas and found that it involves two kinetic mechanisms, the faster of which was diminished by calmodulin (CaM) inhibitors. We developed an analytical model that can be applied to both conventional and ribbon synapses and showed that vesicle resupply is limited by a simple time constant,  = 1/(Ds), where D is the vesicle diffusion coefficient,  is the vesicle diameter,  is the vesicle density, and s is the probability of vesicle attachment. The combination of electrophysiological measurements, modeling, and total internal reflection fluorescence microscopy of single synaptic vesicles suggested that CaM speeds replenishment by enhancing vesicle attachment to the ribbon. Using electroretinogram and whole-cell recordings of light responses, we found that enhanced replenishment improves the ability of cone synapses to signal darkness after brief flashes of light and enhances the amplitude of responses to higherfrequency stimuli. By accelerating the resupply of vesicles to the ribbon, CaM extends the temporal range of synaptic transmission, allowing cones to transmit higher-frequency visual information to downstream neurons. Thus, the ability of the visual system to encode time-varying stimuli is shaped by the dynamics of vesicle replenishment at photoreceptor synaptic ribbons.

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Section: Discussionmentioning

confidence: 99%

Section: R E S U L T Smentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Calmodulin enhances ribbon replenishment and shapes filtering of synaptic transmission by cone photoreceptors

Hook¹,

Parmelee²,

Chen³

et al. 2014

J Cell Biol

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“…For example, the visual system must simultaneously process information about luminance (that is, steady intensity) and contrast (that is, changes in intensity), and the output synapse of the second-order bipolar neurons of the retina is thought to be an important site for the signaling of these two aspects of visual stimuli to downstream neurons (1). The ribbon synapses (2) of bipolar neurons generate both tonic release and phasic release in response to sustained depolarization (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). The phasic component consists of a limited pool of vesicles that can be tapped rapidly upon depolarization but is also rapidly exhausted, generating a transient spike of release, and the tonic component comprises a much larger pool of more slowly released vesicles.…”

mentioning

confidence: 99%

Visualizing synaptic vesicle turnover and pool refilling driven by calcium nanodomains at presynaptic active zones of ribbon synapses

Vaithianathan

Matthews

2014

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

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Ribbon synapses of photoreceptor cells and second-order bipolar neurons in the retina are specialized to transmit graded signals that encode light intensity. Neurotransmitter release at ribbon synapses exhibits two kinetically distinct components, which serve different sensory functions. The faster component is depleted within milliseconds and generates transient postsynaptic responses that emphasize changes in light intensity. Despite the importance of this fast release for processing temporal and spatial contrast in visual signals, the physiological basis for this component is not precisely known. By imaging synaptic vesicle turnover and Ca 2+ signals at single ribbons in zebrafish bipolar neurons, we determined the locus of fast release, the speed and site of Ca 2+ influx driving rapid release, and the location where new vesicles are recruited to replenish the fast pool after it is depleted. At ribbons, Ca 2+ near the membrane rose rapidly during depolarization to levels >10 μM, whereas Ca 2+ at nonribbon locations rose more slowly to the lower level observed globally, consistent with selective positioning of Ca 2+ channels near ribbons. The local Ca 2+ domain drove rapid exocytosis of ribbon-associated synaptic vesicles nearest the plasma membrane, accounting for the fast component of neurotransmitter release. However, new vesicles replacing those lost arrived selectively at the opposite pole of the ribbon, distal to the membrane. Overall, the results suggest a model for fast release in which nanodomain Ca 2+ triggers exocytosis of docked vesicles, which are then replaced by more distant ribbon-attached vesicles, creating opportunities for new vesicles to associate with the ribbon at membrane-distal sites.S ensory systems face the common problem of faithfully encoding the steady intensity of a stimulus over a wide range, while at the same time enhancing the detection of spatial or temporal changes in stimulus intensity. For example, the visual system must simultaneously process information about luminance (that is, steady intensity) and contrast (that is, changes in intensity), and the output synapse of the second-order bipolar neurons of the retina is thought to be an important site for the signaling of these two aspects of visual stimuli to downstream neurons (1). The ribbon synapses (2) of bipolar neurons generate both tonic release and phasic release in response to sustained depolarization (3-12). The phasic component consists of a limited pool of vesicles that can be tapped rapidly upon depolarization but is also rapidly exhausted, generating a transient spike of release, and the tonic component comprises a much larger pool of more slowly released vesicles. The rapid but transient release during the phasic component emphasizes changes in light intensity, whereas the slower but sustained release during the tonic component signals overall luminance (1).Because ribbon synapses are found in sensory neurons that generate sustained responses to stimuli, such as photoreceptor cells and bipolar neurons in the r...

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“…Retinal neurons can also be loaded with fluorescent dyes sensitive to Ca 2+ , Cl -, or Na + introduced through the patch pipette or by bath-application 15,[18][19][20] . A fluorescent peptide that binds to the synaptic ribbon 21 can be introduced through the patch pipette and used for imaging the ribbon 10 or, when conjugated to fluorescein, for acutely and selectively damaging the ribbon 22 . We have also used retinal slices in combination with quantum dots to monitor the movements of individual calcium channels at rod and cone synaptic terminals 23 .…”

Section: Amphibian Saline Presynaptic Pipette Postsynaptic Pipettementioning

confidence: 99%

Simultaneous Whole-cell Recordings from Photoreceptors and Second-order Neurons in an Amphibian Retinal Slice Preparation

Hook

Thoreson

2013

JoVE

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One of the central tasks in retinal neuroscience is to understand the circuitry of retinal neurons and how those connections are responsible for shaping the signals transmitted to the brain. Photons are detected in the retina by rod and cone photoreceptors, which convert that energy into an electrical signal, transmitting it to other retinal neurons, where it is processed and communicated to central targets in the brain via the optic nerve. Important early insights into retinal circuitry and visual processing came from the histological studies of Cajal 1,2 and, later, from electrophysiological recordings of the spiking activity of retinal ganglion cells -the output cells of the retina 3,4 .A detailed understanding of visual processing in the retina requires an understanding of the signaling at each step in the pathway from photoreceptor to retinal ganglion cell. However, many retinal cell types are buried deep in the tissue and therefore relatively inaccessible for electrophysiological recording. This limitation can be overcome by working with vertical slices, in which cells residing within each of the retinal layers are clearly visible and accessible for electrophysiological recording.Here, we describe a method for making vertical sections of retinas from larval tiger salamanders (Ambystoma tigrinum). While this preparation was originally developed for recordings with sharp microelectrodes 5,6 , we describe a method for dual whole-cell voltage clamp recordings from photoreceptors and second-order horizontal and bipolar cells in which we manipulate the photoreceptor's membrane potential while simultaneously recording post-synaptic responses in horizontal or bipolar cells. The photoreceptors of the tiger salamander are considerably larger than those of mammalian species, making this an ideal preparation in which to undertake this technically challenging experimental approach. These experiments are described with an eye toward probing the signaling properties of the synaptic ribbon -a specialized synaptic structure found in a only a handful of neurons, including rod and cone photoreceptors, that is well suited for maintaining a high rate of tonic neurotransmitter release 7,8 -and how it contributes to the unique signaling properties of this first retinal synapse. Video LinkThe video component of this article can be found at https://www.jove.com/video/50007/ Protocol Retinal Slices Preparation1. Assemble the chamber (design illustrated in Figure 1). Place two beads of vacuum grease, spaced ~8-10 mm apart, across the recording chamber to form a channel for superfusate and in which to embed the retinal slices. Add a second bead of grease a few millimeters farther out beyond each of these two beads of grease to act as a levee and limit spillover. Place a small triangular piece of KimWipe at the end of the chamber to ensure fluid contact with the reference electrode. 2. Press a piece of nitrocellulose membrane (~ 5 x 10 mm; 0.8 μm pores) flat against the glass microscope slide into two small beads of vacuum gre...

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Acute destruction of the synaptic ribbon reveals a role for the ribbon in vesicle priming

Cited by 123 publications

References 46 publications

Calmodulin enhances ribbon replenishment and shapes filtering of synaptic transmission by cone photoreceptors

Calmodulin enhances ribbon replenishment and shapes filtering of synaptic transmission by cone photoreceptors

Visualizing synaptic vesicle turnover and pool refilling driven by calcium nanodomains at presynaptic active zones of ribbon synapses

Simultaneous Whole-cell Recordings from Photoreceptors and Second-order Neurons in an Amphibian Retinal Slice Preparation

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