Skipped-Stimulus Approach Reveals That Short-Term Plasticity Dominates Synaptic Strength during Ongoing Activity

Abstract

All synapses show activity-dependent changes in strength, which affect the fidelity of postsynaptic spiking. This is particularly important at auditory nerve synapses, where the presence and timing of spikes carry information about a sound's structure, which must be passed along for proper processing. However, it is not clear how synaptic plasticity influences spiking during ongoing activity. Under these conditions, conventional analyses erroneously suggest that synaptic plasticity has no influence on EPSC amplitude or spiking. Therefore, we developed new approaches to study how ongoing activity influences synaptic strength, using voltage-and current-clamp recordings from bushy cells in brain slices from mouse anteroventral cochlear nucleus. We applied identical trains of stimuli, except for one skipped stimulus, and found that EPSC amplitude was affected for 60 ms following a skipped stimulus. We further showed that the initial probability of release, calcium-dependent mechanisms of recovery, and desensitization all play a role even during ongoing activity. Current-clamp experiments indicated that these processes had a significant effect on postsynaptic spiking, as did the refractory period to a smaller extent. Thus short-term plasticity has real, important functional consequences.

Inhibition in the auditory brainstem enhances signal representation and regulates gain in complex acoustic environments

“…However, also in vitro experiments need to be considered, which showed strong depression at the ANF-SBC synapse (Wang and Manis, 2008; Yang and Xu-Friedman, 2008, 2009; Wang et al, 2010) affecting SBC responsiveness for up to tens of milliseconds (Yang and Xu-Friedman, 2015). Such depression might also suppress SBC spiking in vivo and result in an increased failure fraction during acoustic stimulation.…”

“…Such depression might also suppress SBC spiking in vivo and result in an increased failure fraction during acoustic stimulation. Still, in vivo the impact of depression was shown to be smaller, since ongoing spontaneous activity – completely absent in slice recordings – seems to keep the synapse in a chronically depressed state (Hermann et al, 2007; Lorteije et al, 2009; Yang and Xu-Friedman, 2015). Also, the in vivo calcium concentration was reported to be lower than in the artificial cerebrospinal fluid usually used in slice studies resulting in lower vesicle release probabilities and thus smaller depression (Borst, 2010; Kuenzel et al, 2011; Friauf et al, 2015).…”

“…Considering only the last preceding IEI, however, disregards the potential impact of previous medium- and short-term afferent activity. Also, in vitro studies yielded the influence of short-term depression at the ANF-SBC synapse to extend well beyond the last IEI (Yang and Xu-Friedman, 2015).

10.7554/eLife.19295.005Figure 2.Preceding activity has only a minor, facilitating influence on EPSP rising slopes.( A ) Left : Estimation of threshold EPSP for a representative cell: The EPSP rising slopes were binned (0.5 V/s bin size) and the proportion of EPSP succ calculated for each bin.

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“…Earlier studies showed the influence of preceding neural activity on EPSC/EPSP and AP amplitude (Englitz et al, 2009; Lorteije et al, 2009; Yang and Xu-Friedman, 2015). While usually the preceding inter-event-interval (IEI) is used as a measure of previous activity, recent studies showed that short-term plasticity can extend well beyond the last IEI in vitro (Yang and Xu-Friedman, 2015). Therefore, a weighted average of all preceding events was used, with the impact dependent on the distance and EPSP slope of the respective events.…”

“…For an EPSP slope at t 0 the preceding activity was computed as $PreAct\left(t_0\right)=\frac{1}{median\left(S_i\right)}\underset{i=-1}{\overset{-\infty }{true140\%\sum }}{S}_i{e}^{(t_i-t_0)/\tau }$, with $true0S_i$ indicating the EPSP slopes and $true0t_i$ the temporal distance of the i-th preceding event. The time constant τ was set to 60 ms, as this was shown to be the time window of influence in slice studies (Yang and Xu-Friedman, 2015). In addition, the calculation was also performed with time constants of 10 ms and 100 ms yielding qualitatively the same results.…”