Augmentation Increases Vesicular Release Probability in the Presence of Masking Depression at the Frog Neuromuscular Junction

Abstract

Synaptic augmentation is a short-term component of synaptic plasticity that increases transmitter release during repetitive stimulation and decays thereafter with a time constant of ϳ7 sec. Augmentation has typically been observed under conditions where there is little or no depression because of depletion of synaptic vesicles from the readily releasable pool (RRP) of transmitter. We now study augmentation under conditions of pronounced depression at the frog neuromuscular junction to gain additional insight into mechanism. If augmentation reflects an increase in the size of the RRP of transmitter, then augmentation should not be present with depression. Our findings using four different experimental approaches suggested that augmentation was still present in the presence of pronounced depression: mathematical extraction of augmentation from the changes in transmitter release after repetitive stimulation, identification of augmentation with Ba 2ϩ , correction of the data for the measured depletion of the RRP, and identification of an augmentation component of residual Ca 2ϩ . We conclude that the augmentation machinery still acts to increase transmitter release when depression reduces the RRP sufficiently to mask obvious augmentation. The masked augmentation was found to increase transmitter release by increasing the probability of releasing individual vesicles from the depressed RRP, countering the effects of depression. Because augmentation and depression have similar time courses, either process can mask the other, depending on their relative magnitudes. Consequently, the apparent absence of one of the processes does not exclude that it is still contributing to short-term synaptic plasticity.

The Number of Components of Enhancement Contributing to Short-Term Synaptic Plasticity at the Neuromuscular Synapse during Patterned Nerve Stimulation Progressively Decreases As Basal Release Probability Is Increased from Low to Normal Levels by Changing Extracellular Ca2+

“…Our observations that F1, F2, and A (and also P for the lower range of intermediate prob 0 ) together with a sequential two pool depletion and replacement of vesicles can account for STP at such moderately facilitating synapses (Fig. 2) are consistent with previous descriptions of STP at moderately facilitating excitatory hippocampal synapses (Kandaswamy et al, 2010) and also at moderately facilitating cutaneous pectorus neuromuscular synapses (Kalkstein and Magleby, 2004).…”

“…The RRP is then replenished from a recycling pool (RP). The formulation used for depletion is similar to previous studies Stevens, 1997, 2001;Wu and Betz, 1998;Richards et al, 2003;Kalkstein and Magleby, 2004;Rizzoli and Betz, 2005;Neher and Sakaba, 2008;Pan and Zucker, 2009;Kandaswamy et al, 2010). Depletion occurs because vesicles are released from the RRP faster than they are replaced as follows:…”

“…The model is an extension of the quantal hypothesis proposed by del Castillo and Katz (1954) that often serves as a starting point for more extensive models of transmitter release (Varela et al, 1997;Wu and Borst, 1999;Dittman et al, 2000;Zucker and Regehr, 2002;Trommershäuser et al, 2003;Kalkstein and Magleby, 2004;Pan and Zucker, 2009;Kandaswamy et al, 2010) as follows:…”

“…That F1, F2, A, and P components of miniature EPP frequency (Zengel and Magleby, 1981) are still observed in the presence of depression (Zengel and Sosa, 1994) suggests that the presumed Ca 2ϩ -dependent driving processes for the enhancement components (Kamiya and Zucker, 1994;Tank and Zucker, 1997;Suzuki et al, 2000;Zucker and Regehr, 2002;Kalkstein and Magleby, 2004;García-Chacó n et al, 2006) are still present during marked rundown, but uncoupled from evoked release so that F2, A, and P of evoked release are not detected. The reason for this uncoupling during marked depression is not known but may be related to the fact that spontaneous and evoked release may have differences in location and/or molecular components (Washbourne et al, 2002;Zucker and Regehr, 2002;Maximov and Südhof, 2005;Wadel et al, 2007;Young and Neher, 2009;Yoshihara et al, 2010).…”

A New Kinetic Framework for Synaptic Vesicle Trafficking Tested in Synapsin Knock-Outs

“…Indeed, the large changes in synaptic strength that typically occur before the RRP has been exhausted and the fast rebound seen during subsequent rest intervals are largely caused by additional mechanisms such as RRP depletion (Wesseling and Lo, 2002), heterogeneity in release parameters between release sites (Trommershauser et al, 2003;Moulder and Mennerick, 2005), residual Ca 2ϩ -dependent enhancement of release (Delaney and Tank, 1994;Kalkstein and Magleby, 2004;, and other potential factors (Wadel et al, 2007;Hennig et al, 2008;Mochida et al, 2008).…”