Synaptic Vesicles in Mature Calyx of Held Synapses Sense Higher Nanodomain Calcium Concentrations during Action Potential-Evoked Glutamate Release

Wang, Lu‐Yang; Neher, Erwin; Taschenberger, Holger

doi:10.1523/jneurosci.4245-08.2008

Cited by 124 publications

(174 citation statements)

References 66 publications

(93 reference statements)

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“…Our findings may reconcile this low-flux high-fidelity paradox given that a single Ca V channel would, by virtue of nanodomain Ca 2+ boosting, have the potency of ∼10 channels in the absence of this amplification. Similar implications may apply to presynaptic physiology, where the Ca 2+ dependence of transmitter release has been experimentally determined (20,21,42,43), and the sensitivity to exogenous buffers (EGTA and BAPTA) has been characterized in several preparations (44,45). Whereas these findings are typically interpreted in the context of classical diffusion parameters, our findings may bear upon inferences of Ca V -vesicle distance and stoichiometry.…”

Section: Significancementioning

confidence: 52%

Ca ²⁺ channel nanodomains boost local Ca ²⁺ amplitude

Tadross

Tsien

Yue

2013

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

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Local Ca 2+ signals through voltage-gated Ca 2+ channels (Ca V s) drive synaptic transmission, neural plasticity, and cardiac contraction. Despite the importance of these events, the fundamental relationship between flux through a single Ca V channel and the Ca 2+ signaling concentration within nanometers of its pore has resisted empirical determination, owing to limitations in the spatial resolution and specificity of fluorescence-based Ca 2+ measurements. Here, we exploited Ca 2+ -dependent inactivation of Ca V channels as a nanometer-range Ca 2+ indicator specific to active channels. We observed an unexpected and dramatic boost in nanodomain Ca 2+ amplitude, ten-fold higher than predicted on theoretical grounds. Our results uncover a striking feature of Ca V nanodomains, as diffusion-restricted environments that amplify small Ca 2+ fluxes into enormous local Ca 2+ concentrations. This Ca 2+ tuning by the physical composition of the nanodomain may represent an energy-efficient means of local amplification that maximizes information signaling capacity, while minimizing global Ca 2+ load.L ocal Ca 2+ signals increase the information capacity of signaling within a cell, by enabling short-range signals to operate independently of Ca 2+ events elsewhere throughout the cell (1, 2). These local Ca 2+ signals are the conduit that drives diverse activity-dependent events, such as synaptic transmission (3), neural plasticity (4-6), and cardiac excitation-contraction coupling (7). However, with regard to the Ca 2+ amplitude within nanometers of individual Ca 2+ channels, our knowledge is based predominantly on diffusion theory, which predicts ∼100 μM Ca 2+ signals per picoampere flux at a distance of ∼10 nm from the pore (8-11). Although often quoted, this theory has been difficult to verify experimentally because diffusible Ca 2+ indicators report space-averaged [Ca 2+ ], and thus lack the spatial resolution needed for selective nanodomain reporting. Two recent efforts to overcome this limitation used voltage-gated Ca 2+ channel (Ca V )-tethered fluorescent Ca 2+ indicators to isolate nanodomain signals (12, 13), but were met with unexpected difficulties: Ca V -tethered indicators were unresponsive in the presence of high concentrations of intracellular 1,2-bis(oaminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), a Ca 2+ buffer that preserves Ca 2+ elevations within tens of nanometers of active channels but eliminates it elsewhere (8-10). A lack of response under these conditions would arise if the majority of tethered channels were silent, raising the concern that fluorescence changes observed under milder Ca 2+ buffering (12, 13) may represent the response of indicators tethered to silent channels, which nonetheless eavesdrop on Ca 2+ from active channels nearby. To overcome this fundamental limitation, we used a reverse strategy, whereby Ca 2+ /calmodulin-dependent inactivation (CDI) of channels themselves serves as a nanometer-range indicator of [Ca 2+ ]; a sensitive ionic readout that is unaffected by the pres...

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Section: Significancementioning

confidence: 52%

Ca ²⁺ channel nanodomains boost local Ca ²⁺ amplitude

Tadross

Tsien

Yue

2013

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

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“…Neurotransmitter release relies on a source of calcium and its sensors (Sudhof, 2004). Classical and recent works provide evidence for a close spatial proximity (few nanometers) of calcium channels and vesicular release sites (Adler et al, 1991;Stanley, 1991;Bucurenciu et al, 2008;Wang et al, 2008). This tight coupling has been shown to increase the efficacy, speed, and temporal precision of transmitter release (Fedchyshyn and Wang, 2005;Bucurenciu et al, 2008).…”

Section: Regulation Of Neurotransmitter Content and Release Of Synaptmentioning

confidence: 99%

Vesicular Zinc Regulates the Ca²⁺Sensitivity of a Subpopulation of Presynaptic Vesicles at Hippocampal Mossy Fiber Terminals

Lavoie¹,

Jeyaraju²,

Peralta³

et al. 2011

J. Neurosci.

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Synaptic vesicles segregate into functionally diverse subpopulations within presynaptic terminals, yet there is no information about how this may occur. Here we demonstrate that a distinct subgroup of vesicles within individual glutamatergic, mossy fiber terminals contain vesicular zinc that is critical for the rapid release of a subgroup of synaptic vesicles during increased activity in mice. In particular, vesicular zinc dictates the Ca 2ϩ sensitivity of release during high-frequency firing. Intense synaptic activity alters the subcellular distribution of zinc in presynaptic terminals and decreases the number of zinc-containing vesicles. Zinc staining also appears in endosomes, an observation that is consistent with the preferential replenishment of zinc-enriched vesicles by bulk endocytosis. We propose that functionally diverse vesicle pools with unique membrane protein composition support different modes of transmission and are generated via distinct recycling pathways.

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“…The mature calyx synapse exhibits lower susceptibility to AMPA receptor desensitization (17). During maturation of the calyx of Held, the reduced Ca 2+ influx caused by the shortening of the AP duration is compensated by the tighter spatial coupling of SVs to the calcium source (19,20). It is puzzling, however, that the mature calyx of Held still harbors a large number of SRP vesicles (20,21).…”

Section: Actin Disruption Accelerates Synaptic Depression Of Epscs Evmentioning

confidence: 99%

“…During maturation of the calyx of Held, the reduced Ca 2+ influx caused by the shortening of the AP duration is compensated by the tighter spatial coupling of SVs to the calcium source (19,20). It is puzzling, however, that the mature calyx of Held still harbors a large number of SRP vesicles (20,21). To test whether SRP vesicles are recruited to the phasic release, we examined the effect of latB at the mature calyx synapse in the presence of 2 mM γ-DGG.…”

Section: Actin Disruption Accelerates Synaptic Depression Of Epscs Evmentioning

confidence: 99%

“…Keeping global [Ca 2+ ] low during HFS at presynaptic terminals not only will reduce asynchronous release but also will ensure a rapid supply of SVs from the SRP to the FRP, enhancing phasic release. Compared with the immature calyx of Held, the mature one exhibits more efficient Ca 2+ clearance mechanisms (35,36) and requires less Ca 2+ influx for neurotransmission because of nanodomain coupling (20). These developmental changes may optimize the mature calyx terminal for SDR while minimizing asynchronous release.…”

Section: Srp-dependent Recovery Vs Asynchronous Release Of Reluctantmentioning

confidence: 99%

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Actin-dependent rapid recruitment of reluctant synaptic vesicles into a fast-releasing vesicle pool

Lee

2012

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

105

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Glutamatergic synaptic terminals harbor reluctant synaptic vesicles (SVs) that contribute little to synchronous release during action potentials but are release competent when stimulated by sucrose or by direct intracellular application of calcium. It has been noted that the proximity of a release-competent SV to the calcium source is one of the primary factors that differentiate reluctant SVs from fastreleasing ones at the calyx of Held synapse. It has not been known whether reluctant SVs can be converted into fast-releasing ones. Here we show that reluctant SVs are recruited rapidly in an actindependent manner to become fast-releasing SVs once the pool of fast-releasing SVs is depleted by a short depolarization. Recovery of the pool of fast-releasing SVs was accompanied by a parallel reduction in the number of reluctant SVs. Quantitative analysis of the time course of depletion of fast-releasing SVs during high-frequency stimulation revealed that in the early phase of stimulation reluctant SVs are converted rapidly into fast-releasing ones, thereby counteracting short-term depression. During the late phase, however, after reluctant vesicles have been used up, another process of calmodulindependent recruitment of fast-releasing SVs is activated. These results document that reluctant SVs have a role in short-term plasticity and support the hypothesis of positional priming, which posits that reluctant vesicles are converted into fast-releasing ones via relocation closer to Ca 2+ -channels.readily releasable pool | synaptic vesicle dynamics S ynaptic strength is determined by quantal size, the number of release-competent synaptic vesicles (SVs), and their release probability (Pr). The estimate for the number of release-competent SVs, which also is referred to as the "readily releasable pool (RRP) size," depends heavily on the method used for its determination. The RRP size estimated by a cumulative plot of the excitatory postsynaptic currents (EPSC) amplitudes evoked by high-frequency afferent fiber stimulation (RRP cum ) is smaller than that estimated by the application of a hypertonic sucrose solution or presynaptic strong depolarization (1-3). This discrepancy reflects the presence of reluctant SVs, which are scarcely released by an action potential (AP) at glutamatergic synaptic terminals. Consistently, deconvolution analysis of EPSCs evoked by a long depolarizing pulse at the calyx of Held revealed that release-competent SVs can be separated into fast-and slowreleasing SV pools (FRP and SRP, respectively) (4). The FRP vesicles are responsible for phasic release during a high-frequency train of action potentials (APs), whereas the SRP vesicles contribute primarily to asynchronous release, when the intracellular concentration of calcium ions ([Ca 2+ ]) is increased globally during the late period of the train (2). Thus, SRP vesicles can be regarded largely as reluctant SVs at the calyx of Held.Despite the evidence for the presence of reluctant SVs at glutamatergic synapses, their role in short-term plasticity i...

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Synaptic Vesicles in Mature Calyx of Held Synapses Sense Higher Nanodomain Calcium Concentrations during Action Potential-Evoked Glutamate Release

Cited by 124 publications

References 66 publications

Ca ²⁺ channel nanodomains boost local Ca ²⁺ amplitude

Ca ²⁺ channel nanodomains boost local Ca ²⁺ amplitude

Vesicular Zinc Regulates the Ca²⁺Sensitivity of a Subpopulation of Presynaptic Vesicles at Hippocampal Mossy Fiber Terminals

Actin-dependent rapid recruitment of reluctant synaptic vesicles into a fast-releasing vesicle pool

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Synaptic Vesicles in Mature Calyx of Held Synapses Sense Higher Nanodomain Calcium Concentrations during Action Potential-Evoked Glutamate Release

Cited by 124 publications

References 66 publications

Ca 2+ channel nanodomains boost local Ca 2+ amplitude

Ca 2+ channel nanodomains boost local Ca 2+ amplitude

Vesicular Zinc Regulates the Ca2+Sensitivity of a Subpopulation of Presynaptic Vesicles at Hippocampal Mossy Fiber Terminals

Actin-dependent rapid recruitment of reluctant synaptic vesicles into a fast-releasing vesicle pool

Contact Info

Product

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Ca ²⁺ channel nanodomains boost local Ca ²⁺ amplitude

Ca ²⁺ channel nanodomains boost local Ca ²⁺ amplitude

Vesicular Zinc Regulates the Ca²⁺Sensitivity of a Subpopulation of Presynaptic Vesicles at Hippocampal Mossy Fiber Terminals