Presynaptic fluctuations and release-independent depression

Abstract

Although vesicle depletion contributes to short-term depression, several studies have reported that the release probability can be transiently depressed even if an action potential fails to evoke release. Here we argue that stochastic fluctuation in the release machinery can give rise to apparent release-independent depression as a result of sampling bias. The relationship between this apparent depression and the interstimulus interval provides a window on the kinetics of state transitions of the release apparatus.Synapses almost universally show a dependence of release probability on the recent history of activity: they facilitate or depress, and a number of mechanisms contribute to this phenomenon, most prominent of which are postspike elevations of the calcium concentration in the presynaptic terminal and the depletion of readily releasable vesicles 1 . However, an intriguing phenomenon has been revealed by several studies that looked at individual synapses with very short interstimulus intervals (<10-15 ms): the probability of observing a quantal release event seems to be profoundly decreased following the second stimulus, not only when the first stimulus resulted in a release event, but also sometimes when it resulted in a failure of release ( Fig. 1 and refs. 2,3).'Release-independent depression' is typically demonstrated by repeatedly probing the synapse with paired stimuli and sorting the results into several outcomes. Let us denote the probability of observing two failures as P(0,0), a failure followed by a success as P(0,1), a success followed by a failure as P(1,0), and two successes as P(1,1). The reported result is that the success rate for the second response, if the first stimulus resulted in a failure, is lower than the overall success rate for the first stimulus: that is, P(0,1)/(P(0,0) + P(0,1)) < P(1,0) + P(1,1). In other words, P[R 2 |F 1 ], the conditional probability of observing release for the second stimulus when there was a failure at the first stimulus, is smaller than P[R 1 ], the overall average probability of release for the first stimulus (Fig. 1b).Several mechanisms have been proposed to underlie release-independent depression, including failure of action potential invasion 4 and Ca 2+ channel inactivation 2,3 , although none of these has been conclusively demonstrated. We argue here that release-independent depression may actually be illusory, resulting from the assumption that the initial state of the synapse is constant across all trials.To illustrate this idea, let us first consider the following analogy. Let us assume that you like to fish, but because you are also a busy scientist, you set yourself a rule that each time you go fishing you will only cast the line twice before packing up to go back to the lab. You may

Short-term plasticity constrains spatial organization of a hippocampal presynaptic terminal

“…Several experimental studies have considered the response to the second stimulus in a paired-pulse protocol when the response to the first pulse was a success (p 11 ) and when response to the first stimulus was a failure (p 01 ), reaching different conclusions (35)(36)(37)(38)(39)(40). Both p 01 greater than p 11 (29,37,41) and p 01 to be less than p 11 (35,36) have been reported.…”

Hybrid Markov-mass action law model for cell activation by rare binding events: Application to calcium induced vesicular release at neuronal synapses

“…However, the release mechanism is not well understood and computing the release probability remains a challenge 12 13 14 15 . The mechanism is described as follows: after an action potential invades the pre-synaptic terminal, voltage-gated calcium channels (VGCCs) open, leading to a calcium influx into the pre-synaptic domain 8 16 17 . When several diffusing calcium ions have succeeded to find small molecular targets, which form a complex of molecular machinery (such as synaptotagmin and any other key molecules) located underneath a vesicle, these molecules are changing their conformation, activating the fusion of the vesicle with the cell membrane and thus triggering the release of neurotransmitters 11 .…”

Measuring action potential-evoked transmission at individual synaptic contacts

“…At no synapse studied was there a significant impact of first response success on second response success (Fisher’s exact test p -values 0.53, 0.29, 0.10, 0.60 and 1.00, respectively, for synapses from top to bottom). As the failure rate in response to the first presynaptic AP was generally higher, we then considered this rate based on the success or failure of the second pulse as a test for a fluctuating synaptic state (Volynski et al 2006) that might affect the release dependence result (figure 5(A); Fisher’s exact test p -values the same, as second pulse success/failure given first pulse success/failure is the transposed matrix of first pulse success/failure given second pulse success/failure). The absence of such a relationship is consistent with fluctuations in the synaptic state having no effect on responses at the 50 ms IPI used here.…”