Modeling and measurement of vesicle pools at the cone ribbon synapse: Changes in release probability are solely responsible for voltage‐dependent changes in release

Thoreson, Wallace B.; Hook, Matthew J. Van; Parmelee, Caitlyn; Curto, Carina

doi:10.1002/syn.21871

Cited by 19 publications

(21 citation statements)

References 51 publications

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“…The amplitude of the PSC evoked by the initial step to À30 mV was similar between stx3pep and stx3con cone photoreceptors ( Fig. 9 C, (65) and so this result indicates that the RRP was not significantly affected by stx3pep. With a maintained train of pulses, the entire RRP and RP are both ultimately released.…”

Section: Stx3pep Inhibits the Recruitment Of New Vesicles To The Synamentioning

confidence: 58%

“…At the cone-horizontal cell synapse in salamander retina, postsynaptic currents (PSCs) are assembled from a linear sum of individual m-excitatory postsynaptic potentials (63,64), allowing us to use charge transfer as a measure of vesicle release. Integrating the total charge transfer of the horizontal cell PSC (Q PSC ) evoked by stimulation of a cone with the train yields a rapid increase in charge transfer reflecting synchronous release from the cone RRP followed by a second slower release of the RP (16,65) (Fig. 9 A).…”

Section: Stx3pep Inhibits the Recruitment Of New Vesicles To The Synamentioning

confidence: 99%

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Two Pools of Vesicles Associated with Synaptic Ribbons Are Molecularly Prepared for Release

Datta

Gilliam

Thoreson

et al. 2017

Biophysical Journal

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Neurons that form ribbon-style synapses are specialized for continuous exocytosis. To this end, their synaptic terminals contain numerous synaptic vesicles, some of which are ribbon associated, that have difference susceptibilities for undergoing Ca-dependent exocytosis. In this study, we probed the relationship between previously defined vesicle populations and determined their fusion competency with respect to SNARE complex formation. We found that both the rapidly releasing vesicle pool and the releasable vesicle pool of the retinal bipolar cell are situated at the ribbon-style active zones, where they functionally interact. A peptide inhibitor of SNARE complex formation failed to block exocytosis from either pool, suggesting that these two vesicle pools have formed the SNARE complexes necessary for fusion. By contrast, a third, slower component of exocytosis was blocked by the peptide, as was the functional replenishment of vesicle pools, indicating that few vesicles outside of the ribbon-style active zones were initially fusion competent. In cone photoreceptors, similar to bipolar cells, fusion of the initial ribbon-associated synaptic vesicle cohort was not blocked by the SNARE complex-inhibiting peptide, whereas a later phase of exocytosis, attributable to the recruitment and subsequent fusion of vesicles newly arrived at the synaptic ribbons, was blocked. Together, our results support a model in which stimulus-evoked exocytosis in retinal ribbon synapses is SNARE-dependent; where vesicles higher up on the synaptic ribbon replenish the rapidly releasing vesicle pool; and at any given time, there are sufficient SNARE complexes to support the fusion of the entire ribbon-associated cohort of vesicles. An important implication of these results is that ribbon-associated vesicles can form intervesicular SNARE complexes, providing mechanistic insight into compound fusion at ribbon-style synapses.

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Section: Stx3pep Inhibits the Recruitment Of New Vesicles To The Synamentioning

confidence: 58%

Section: Stx3pep Inhibits the Recruitment Of New Vesicles To The Synamentioning

confidence: 99%

Two Pools of Vesicles Associated with Synaptic Ribbons Are Molecularly Prepared for Release

Datta

Gilliam

Thoreson

et al. 2017

Biophysical Journal

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“…Horizontal cells have larger light responses and larger dendritic fields than OFF-bipolar cells, so HCs are likely to receive more photoreceptor contacts than OFF-bipolar cells. In cones, there appear to be~15-20 vesicle release sites at the base of each ribbon (Bartoletti et al, 2010;Thoreson et al, 2016). In rods, the readily releasable pool averages 24 vesicles/ribbon (Van Hook & Thoreson, 2015).…”

Section: Functional Impact Of Spontaneous Releasementioning

confidence: 99%

Mechanisms, pools, and sites of spontaneous vesicle release at synapses of rod and cone photoreceptors

Cork

Hook

Thoreson

2016

Eur J of Neuroscience

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Photoreceptors have depolarized resting potentials that stimulate calcium-dependent release continuously from a large vesicle pool but neurons can also release vesicles without stimulation. We characterized the Ca2+ dependence, vesicle pools, and release sites involved in spontaneous release at photoreceptor ribbon synapses. In whole cell recordings from light-adapted horizontal cells (HCs) of tiger salamander retina, we detected miniature excitatory post-synaptic currents (mEPSCs) when no stimulation was applied to promote exocytosis. Blocking Ca2+ influx by lowering extracellular Ca2+, by application of Cd2+ and other agents reduced the frequency of mEPSCs but did not eliminate them, indicating that mEPSCs can occur independently of Ca2+. We also measured release presynaptically from rods and cones by examining quantal glutamate transporter anion currents. Presynaptic quantal event frequency was reduced by Cd2+ or by increased intracellular Ca2+ buffering in rods, but not in cones, that were voltage-clamped at −70 mV. By inhibiting the vesicle cycle with bafilomycin, we found the frequency of mEPSCs declined more rapidly than the amplitude of evoked EPSCs suggesting a possible separation between vesicle pools in evoked and spontaneous exocytosis. We mapped sites of Ca2+-independent release using total internal reflectance fluorescence (TIRF) microscopy to visualize fusion of individual vesicles loaded with dextran-conjugated pHrodo. Spontaneous release in rods occurred more frequently at non-ribbon sites than evoked release events. The function of Ca2+-independent spontaneous release at continuously active photoreceptor synapses remains unclear, but the low frequency of spontaneous quanta limits their impact on noise.

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“…For the cone model, r msr was set to 100 vesicles per second based on 57 . The prior for v max RRP was based on RRP sizes reported for salamander 58,59 . For the BCs, r msr was set to 8 vesicles per second based on the reported value for rat rod bipolar cells in 60 .…”

Section: Neurotransmitter Releasementioning

confidence: 99%

Bayesian inference for biophysical neuron models enables stimulus optimization for retinal neuroprosthetics

Oesterle

Behrens

Schroeder

et al. 2020

Preprint

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Multicompartment models have long been used to study the biophysical mechanisms underlying neural information processing. However, it has been challenging to infer the parameters of such models from data. Here, we build on recent advances in Bayesian simulation-based inference to estimate the parameters of detailed models of retinal neurons whose anatomical structure was based on electron microscopy data. We demonstrate how parameters of a cone, an OFF-and an ON-cone bipolar cell model can be inferred from standard two-photon glutamate imaging with simple light stimuli. The inference method starts with a prior distribution informed by literature knowledge and yields a posterior distribution over parameters highlighting parameters consistent with the data. This posterior allows determining how well parameters are constrained by the data and to what extent changes in one parameter can be compensated for by changes in another. To demonstrate the potential of such data-driven mechanistic neuron models, we created a simulation environment for external electrical stimulation of the retina as used in retinal neuroprosthetic devices. We used the framework to optimize the stimulus waveform to selectively target OFFand ON-cone bipolar cells, a current major problem of retinal neuroprothetics. Taken together, this study demonstrates how a data-driven Bayesian simulation-based inference approach can be used to estimate parameters of complex mechanistic models with high-throughput imaging data.Constraining many of these model parameters such as channel densities requires highly specialized and technically challenging experiments, and, hence, it is usually not viable to measure every single parameter for a neuron model of a specific neuron type. Rather, parameters for mechanistic simulations are often aggregated over different neuron types and even across species. Even though this may be justified in specific cases it likely limits our ability to identify mechanistic models of individual cell types. Alternatively, parameter search methods have been proposed to identify the parameters of mechanistic neuron models from standardized patch-clamp protocols based on exhaustive grid-searches 9-11 or evolutionary algorithms [12][13][14][15] . Such methods are often inefficient, typically not applicable for models with many parameters and identify only a single point estimate consistent with the data instead of the entire distribution.Here, we built on recent advances in Bayesian simulation-based inference to fit multicompartment models of neurons with realistic anatomy in the mouse retina. We used a framework called Sequential Neural Posterior Estimation (SNPE) 16,17 to identify model parameters based on high-throughput two-photon measurements of these neurons' responses to light stimuli. SNPE is a Bayesian simulation-based inference algorithm that allows parameter estimation for simulator models for which the likelihood cannot be evaluated easily. The algorithm estimates the distribution of model parameters consistent with specified ...

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Modeling and measurement of vesicle pools at the cone ribbon synapse: Changes in release probability are solely responsible for voltage‐dependent changes in release

Cited by 19 publications

References 51 publications

Two Pools of Vesicles Associated with Synaptic Ribbons Are Molecularly Prepared for Release

Two Pools of Vesicles Associated with Synaptic Ribbons Are Molecularly Prepared for Release

Mechanisms, pools, and sites of spontaneous vesicle release at synapses of rod and cone photoreceptors

Bayesian inference for biophysical neuron models enables stimulus optimization for retinal neuroprosthetics

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