Dynamic Control of Synaptic Vesicle Replenishment and Short-Term Plasticity by Ca2+-Calmodulin-Munc13-1 Signaling

Lipstein, Noa; Sakaba, Takeshi; Cooper, Benjamin H.; Lin, Kun-Han; Strenzke, Nicola; Ashery, Uri; Rhee, Jeong−Seop; Taschenberger, Holger; Neher, Erwin; Brose, Nils

doi:10.1016/j.neuron.2013.05.011

Cited by 145 publications

(172 citation statements)

References 71 publications

Supporting

Mentioning

154

Contrasting

Unclassified

Order By: Relevance

“…Sample eEPSC trains are shown in Figure 6A. Consistent with previous reports, eEPSC trains of wt calyx synapses showed mostly depression (Erazo-Fischer et al, 2007;Lipstein et al, 2013). In contrast, eEPSCs of Cplx1 Ϫ/Ϫ calyx synapses (n ϭ 50, P16 -P21) initially strongly facilitated.…”

Section: Comparison Of Short-term Plasticity In Calyx Synapses Of Cplx1supporting

confidence: 88%

Complexin Stabilizes Newly Primed Synaptic Vesicles and Prevents Their Premature Fusion at the Mouse Calyx of Held Synapse

et al. 2015

View full text Add to dashboard Cite

Complexins (Cplxs) are small synaptic proteins that cooperate with SNARE-complexes in the control of synaptic vesicle (SV) fusion. Studies involving genetic mutation, knock-down, or knock-out indicated two key functions of Cplx that are not mutually exclusive but cannot easily be reconciled, one in facilitating SV fusion, and one in "clamping" SVs to prevent premature fusion. Most studies on the role of Cplxs in mammalian synapse function have relied on cultured neurons, heterologous expression systems, or membrane fusion assays in vitro, whereas little is known about the function of Cplxs in native synapses. We therefore studied consequences of genetic ablation of Cplx1 in the mouse calyx of Held synapse, and discovered a developmentally exacerbating phenotype of reduced spontaneous and evoked transmission but excessive asynchronous release after stimulation, compatible with combined facilitating and clamping functions of Cplx1. Because action potential waveforms, Ca 2ϩ influx, readily releasable SV pool size, and quantal size were unaltered, the reduced synaptic strength in the absence of Cplx1 is most likely a consequence of a decreased release probability, which is caused, in part, by less tight coupling between Ca 2ϩ channels and docked SV. We found further that the excessive asynchronous release in Cplx1-deficient calyces triggered aberrant action potentials in their target neurons, and slowed-down the recovery of EPSCs after depleting stimuli. The augmented asynchronous release had a delayed onset and lasted hundreds of milliseconds, indicating that it predominantly represents fusion of newly recruited SVs, which remain unstable and prone to premature fusion in the absence of Cplx1.

show abstract

Section: Comparison Of Short-term Plasticity In Calyx Synapses Of Cplx1supporting

confidence: 88%

Complexin Stabilizes Newly Primed Synaptic Vesicles and Prevents Their Premature Fusion at the Mouse Calyx of Held Synapse

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Alternatively, a conformational change within Munc13s, induced by the modulators, may underlie superpriming. This possibility is supported by recent studies, which show that mutations in the regulatory domains of Munc13-1 enhance the baseline release probability of SVs (9,21).…”

Section: Discussionmentioning

confidence: 54%

“…Similar to CaM inhibitors, perturbations of proteins involved in endocytosis have a specific effect on CDR, implying that CaM-dependent CDR is closely related to clearing refractory release sites (22). Recently, a knock-in mouse line was established that harbors a CaM-insensitive mutant of Munc13-1 (21). It was shown that recovery of the FRP after prolonged depolarization is slowed down in calyces of such mice, mimicking block of CDR.…”

Section: Discussionmentioning

confidence: 99%

Superpriming of synaptic vesicles after their recruitment to the readily releasable pool

Lee

Neher

et al. 2013

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

Self Cite

103

View full text Add to dashboard Cite

Recruitment of release-competent vesicles during sustained synaptic activity is one of the major factors governing short-term plasticity. During bursts of synaptic activity, vesicles are recruited to a fast-releasing pool from a reluctant vesicle pool through an actin-dependent mechanism. We now show that newly recruited vesicles in the fast-releasing pool do not respond at full speed to a strong Ca 2+ stimulus, but require approximately 4 s to mature to a "superprimed" state. Superpriming was found to be altered by agents that modulate the function of unc13 homolog proteins (Munc13s), but not by calmodulin inhibitors or actin-disrupting agents. These findings indicate that recruitment and superpriming of vesicles are regulated by separate mechanisms, which require integrity of the cytoskeleton and activation of Munc13s, respectively. We propose that refilling of the fast-releasing vesicle pool proceeds in two steps, rapid actin-dependent "positional priming," which brings vesicles closer to Ca 2+ sources, followed by slower superpriming, which enhances the Ca 2+ sensitivity of primed vesicles.T he release rate of a synaptic vesicle (SV) is governed by two factors, the intrinsic Ca 2+ sensitivity of the vesicle fusion machinery and the distance of the SV to Ca 2+ channels. As Munc13s and Munc18s confer fusion competence on a docked SV, the regulation of release rate by Munc13s and Munc18s is called "molecular priming" (1). It is distinguished from "positional priming," a process that is thought to regulate the proximity of an SV to the calcium source (2, 3). However, it is not known how these two priming mechanisms are manifested in the kinetics of quantal release. Deconvolution analyses of excitatory postsynaptic currents (EPSCs) evoked by long presynaptic depolarizations at the calyx of Held (a giant nerve terminal in the auditory pathway) showed that releasable SVs can be separated into fastreleasing pools (FRPs) and slowly releasing pools (SRPs) (4). The differences in SV priming that underlie the differences in release kinetics between SVs in the FRP and the SRP are currently unclear (3, 5). Wadel et al. (3) found that SVs in the SRP can be released by homogenous Ca 2+ elevation only 1.5 to 2 times slower than SVs in the FRP, even though they are released 10 times slower by depolarization-induced Ca 2+ influx. This was interpreted as evidence that the differences in their release kinetics arise from differences primarily in positional priming. In contrast, Wölfel et al. (5) showed that release with two kinetic components is even observed if the intracellular Ca 2+ concentration is homogenously elevated throughout the calyx terminal, indicating that SVs in the FRP and the SRP differ with regard to their molecular priming.We found recently that SVs in the SRP rapidly convert into the FRP after specific FRP depletion by a short depolarizing pulse (6). Such rapid refilling of the FRP with SRP vesicles, which is referred to as SRP-dependent recovery (SDR), was suppressed by actin depolymerization or inhibition ...

show abstract

“…However, unlike the calyx of Held where CaM appears to act via Munc13 to enhance vesicle priming at the membrane (Z. Lipstein et al, 2013), our results suggest that CaM acts on ribbon-associated proteins to increase the likelihood that vesicles attach to ribbons. Furthermore, by disrupting CaM, we found that Ca 2+ -dependent replenishment accelerates replenishment in cones over short time intervals and thus plays an important role in setting the high-frequency fall off of cone synaptic transmission.…”

Section: Patch-clamp Electrophysiologymentioning

confidence: 63%

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

Hook¹,

Parmelee²,

Chen³

et al. 2014

J Cell Biol

View full text Add to dashboard Cite

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.

show abstract

Dynamic Control of Synaptic Vesicle Replenishment and Short-Term Plasticity by Ca2+-Calmodulin-Munc13-1 Signaling

Cited by 145 publications

References 71 publications

Complexin Stabilizes Newly Primed Synaptic Vesicles and Prevents Their Premature Fusion at the Mouse Calyx of Held Synapse

Complexin Stabilizes Newly Primed Synaptic Vesicles and Prevents Their Premature Fusion at the Mouse Calyx of Held Synapse

Superpriming of synaptic vesicles after their recruitment to the readily releasable pool

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

Contact Info

Product

Resources

About