Superpriming of synaptic vesicles as a common basis for intersynapse variability and modulation of synaptic strength

Abstract

Glutamatergic synapses show large variations in strength and shortterm plasticity (STP). We show here that synapses displaying an increased strength either after posttetanic potentiation (PTP) or through activation of the phospholipase-C-diacylglycerol pathway share characteristic properties with intrinsically strong synapses, such as (i) pronounced short-term depression (STD) during high-frequency stimulation; (ii) a conversion of that STD into a sequence of facilitation followed by STD after a few conditioning stimuli at low frequency; (iii) an equalizing effect of such conditioning stimulation, which reduces differences among synapses and abolishes potentiation; and (iv) a requirement of long periods of rest for reconstitution of the original STP pattern. These phenomena are quantitatively described by assuming that a small fraction of "superprimed" synaptic vesicles are in a state of elevated release probability (p ∼ 0.5). This fraction is variable in size among synapses (typically about 30%), but increases after application of phorbol ester or during PTP. The majority of vesicles, released during repetitive stimulation, have low release probability (p ∼ 0.1), are relatively uniform in number across synapses, and are rapidly recruited. In contrast, superprimed vesicles need several seconds to be regenerated. They mediate enhanced synaptic strength at the onset of burst-like activity, the impact of which is subject to modulation by slow modulatory transmitter systems.posttetanic potentiation | short-term plasticity | calyx of Held | Munc13 | phorbol ester G lutamatergic synapses display a variety of dynamic changes in response to stimulation with action potential (AP) trains, ranging from immediate short-term depression to facilitation followed by depression (1). Both pharmacological (2-6) and molecular (7-9) perturbations have been described, which change such patterns from one to the other in a given synapse. Short-term plasticity (STP) has been shown to underlie many basic signal processing tasks of circuits in the central nervous system (10-13) and rapid changes of STP have been considered "... to be an almost necessary condition for the existence of (short-lived) activity states in the central nervous system" (ref. 14, p. 247). The balance between facilitation and depression is shifted during posttetanic potentiation (PTP) (15) and behavioral states are dynamically regulated by STP (16). Regulation occurs through slow, modulatory transmitter systems (17, 18). However, many open questions regarding the mechanisms underlying such changes remain. Modulation of presynaptic voltage-gated Ca 2+ channels by slow transmitter systems is probably the most powerful mechanism of changing release probability (p) of synaptic vesicles (SVs) (19)(20)(21). Changes in intrinsic [Ca 2+ ] i sensitivity of the release apparatus also contribute and have been investigated in the context of the phospholipase-C-diacylglycerol (PLC-DAG) signaling pathway (22-26) and posttetanic potentiation (15,(27)(28)(29)(30), but the infl...

Input timing for spatial processing is precisely tuned via constant synaptic delays and myelination patterns in the auditory brainstem

“…Differential calcium buffering has been suggested for lateral vs. medial calyx of Held synapses, which resulted in larger excitatory postsynaptic currents (EPSCs) in lateral MNTB neurons and might also contribute to more stable transmission in ongoing responses described in this present study (45). Additionally, an elevated state of release probability of synaptic vesicles, recently shown for the onset events in MNTB (46), may also be available in the ongoing response in neurons tuned to lower frequencies of the gerbil. However, because most research on the calyx of Held had been performed in mice or rats but not in ITD-using animals like gerbils (47) or guinea pigs (48), one can only speculate how constant synaptic delays are achieved in the subpopulation described above.…”

A C1-C2 Module in Munc13 Inhibits Calcium-Dependent Neurotransmitter Release

“…Each SV in the RRP has an intrinsic fusogenicity, and this property is apparently heterogeneous within the synapse (Ariel et al, 2013; Herman and Rosenmund, 2015; Lee et al, 2013; Nakamura et al, 2015; Rosenmund et al, 1993; Schlüter et al, 2006; Taschenberger et al, 2016). In particular, a subset of primed vesicles has been proposed to be in a “superprimed” state with a significantly higher release probability than the remainder of the SVs (Lee et al, 2013; Schlüter et al, 2006; Taschenberger et al, 2016). A recent study revealed that the superprimed pool of SVs is enhanced by phorbol esters, and this pool was transiently expanded following high-frequency stimulation, thereby contributing to post-tetanic potentiation (PTP) (Taschenberger et al, 2016).…”

“…In particular, a subset of primed vesicles has been proposed to be in a “superprimed” state with a significantly higher release probability than the remainder of the SVs (Lee et al, 2013; Schlüter et al, 2006; Taschenberger et al, 2016). A recent study revealed that the superprimed pool of SVs is enhanced by phorbol esters, and this pool was transiently expanded following high-frequency stimulation, thereby contributing to post-tetanic potentiation (PTP) (Taschenberger et al, 2016). Our data along with previous studies support an important post-priming function of Munc13 (Basu et al, 2007; Lou et al, 2008; Madison et al, 2005; Rhee et al, 2002).…”

Numbers of presynaptic Ca 2+ channel clusters match those of functionally defined vesicular docking sites in single central synapses

“…S2). Monte Carlo simulations of these results indicated that, at 4 wk, the release probability of docked SVs is reduced for the first and second stimulation, possibly reflecting a decrease of the percentage of high release probability "superprimed" SVs (39,40). In addition, simulations indicated a reduction of the initial occupancy of the replacement site at 4 wk (Fig.…”