Abstract
Previously, we showed that modulation of the energy barrier for synaptic vesicle fusion boosts release rates supralinearly (Schotten, 2015). Here we show that mouse hippocampal synapses employ this principle to trigger Ca2+-dependent vesicle release and post-tetanic potentiation (PTP). We assess energy barrier changes by fitting release kinetics in response to hypertonic sucrose. Mimicking activation of the C2A domain of the Ca2+-sensor Synaptotagmin-1 (Syt1), by adding a positive charge (Syt1D232N) or increasing its hydrophobicity (Syt14W), lowers the energy barrier. Removing Syt1 or impairing its release inhibitory function (Syt19Pro) increases spontaneous release without affecting the fusion barrier. Both phorbol esters and tetanic stimulation potentiate synaptic strength, and lower the energy barrier equally well in the presence and absence of Syt1. We propose a model where tetanic stimulation activates Syt1-independent mechanisms that lower the energy barrier and act additively with Syt1-dependent mechanisms to produce PTP by exerting multiplicative effects on release rates.
Highlights
Synaptic transmission is a highly dynamic process
Syt1 may inhibit a second high-affinity Ca2+sensor [15,28], reducing sensitivity to local Ca2+-fluctuations [32,33,34], but likely not affecting the energy barrier. To discriminate between these two possibilities, we investigated whether the energy barrier in a resting synapse was altered in the absence of Syt1, comparing wild type (WT) and Syt1 KO glutamatergic hippocampal neurons
Voltage clamp recordings revealed that spontaneous miniature excitatory post-synaptic current frequency was more than doubled (Fig. 1E), while first evoked EPSC charge was strongly reduced in Syt1 KO synapses, compared with WT (Fig. 1F,G)
Summary
Synaptic transmission is a highly dynamic process. Vesicle release rates change several orders of magnitude in response to Ca2+ influx [1,2], and during repeated synaptic activity, the number of vesicles released by an action potential (AP) rapidly change [3]. Synaptic vesicle release is tightly controlled by specialized proteins, including SNAREs, SM proteins, and Ca2+-sensors, among others [4] Many of these are involved in the last step of the release process in which the fusion of the lipid membranes of the vesicle and presynaptic terminal occurs. Synaptotagmin-7 has been shown to trigger asynchronous release [22,23,24], but is identified as a Ca2+ sensor for short-term facilitation [25,26] The latter has been proposed to be due to its concerted action with Syt on the fusion energy barrier [7,25,27]
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