Post-tetanic potentiation lowers the energy barrier for synaptic vesicle fusion independently of Synaptotagmin-1

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 dependent and independent mechanisms that lower the energy barrier independently in an additive manner to produce PTP by multiplication of release rates.

Deconstructing Synaptotagmin-1's Distinct Roles in Synaptic Vesicle Priming and Neurotransmitter Release

“…In this study, we iterated the existence of three different synaptic functions performed by SYT1 using an autaptic primary neuronal culture model. Previous results concerning the ability of SYT1 to promote SV docking/priming (Geppert et al, 1994;Jorgensen et al, 1995;Reist et al, 1998;Nagy et al, 2006;Liu et al, 2009;Bacaj et al, 2013Bacaj et al, , 2015Imig et al, 2014;Chang et al, 2018;Huson et al, 2020) and spontaneous release clamping (DiAntonio and Schwarz, 1994;Geppert et al, 1994;Littleton et al, 1994;Mackler et al, 2002;Yoshihara and Littleton, 2002;Chicka et al, 2008;Liu et al, 2009;Xu et al, 2009;Bacaj et al, 2013;Wierda and Sørensen, 2014) have been contradictory. Here, we demonstrated that SYT1 has a role in SV priming and clamping spontaneous release, which becomes essential over neuronal maturation.…”

“…SYT7 has been suggested as the calcium sensor for asynchronous release (Maximov et al, 2008;Bacaj et al, 2013;Luo et al, 2015;Turecek and Regehr, 2018). SYT7 has also been proposed as a mediator of short-term facilitation of transmission during repetitive stimulation (Wen et al, 2010;Jackman et al, 2016;Chen et al, 2017b;Fujii et al, 2021), involving a mechanism of SYT7's concerted action with SYT1 on the fusion energy barrier (Schotten et al, 2015;Chen et al, 2017b;Jackman and Regehr, 2017;Huson et al, 2020). Supporting its role as a calcium sensor, SYT7 contributes to regulated exocytosis in chromaffin and pancreatic cells (Sugita et al, 2001;Shin et al, 2002;Schonn et al, 2008;Bendahmane et al, 2020).…”

A de novo missense mutation in synaptotagmin-1 associated with neurodevelopmental disorder desynchronizes neurotransmitter release

“…Interestingly, dendrites of single Syt1 PL -expressing neurons embedded in a mass culture of wild type cells developed normally, presumably receiving normal synaptic input from neighboring neurons, suggesting that the morphological changes are secondary to the electrophysiological phenotype. We speculate that this could be a homeostatic adaptation speci cally to the exceptionally high spontaneous release rates beyond KO levels and/or increased AP-induced total release per synapse in these neurons 42 , since no morphological defects were reported for Syt1 KO neurons 43 .…”

“…Abnormalities in dendritic growth have been proposed to be some of the major defects in ASD 51,52 , and may be underlying suggested differences in long-range versus short-range connections in ASD 53,54 . Several cell models for neurodevelopmental disorders display either shortened 6, 55-59 or elongated 55,60,61 dendrites, however, dendritic abnormalities are absent in Syt1 KO neurons 43 , and have not been associated with Syt1 disease mutations reported so far 7,22,23 .…”