Biophysical Society Conference | Estes Park 2023

Membrane Budding and Fusion

Poster Abstracts

12-POS Board 4 A BIOPHYSICAL MODEL OF SYNAPTIC VESICLE FUSION BASED ON BINDING OF DIFFERENT SYNAPTOTAGMIN ISOFORMS

Dennis J Weingarten 1 ; Chloé Le Moing 1 ; Amita Shrestha 1 ; Skyler L Jackman 1 ; 1 Oregon Health & Science University, Vollum Institute, Portland, OR, USA

Chemical synapses are the predominant signaling pathway between neurons in the brain. In these synapses, the Ca 2+ -sensing protein synaptotagmin-1 (SYT1) triggers the synchronous fusion of synaptic vesicles with the presynaptic plasma membrane after an action potential. In addition, we recently showed that isoforms SYT3 and SYT7 play crucial roles in modulating this release to enhance and maintain synaptic responses (Jackman et al., 2016, Nature; Weingarten et al., 2022, Nature). However, the molecular mechanism of both SYT3 and SYT7 and their relation to SYT1 still remains unknown. To uncover the exact role of these SYTs in synaptic vesicle fusion, we performed whole-cell electrophysiological recordings in multiple brain regions (cerebellum, hippocampus, and brainstem) in acute brain slices generated from transgenic mice lacking either SYT3 or SYT7, or both. Subsequently, we employed multiple biophysical models of synaptic vesicle trafficking and fusion to unravel the role of both SYTs in vesicle release and synaptic plasticity. We found that synapses lacking either SYT3 or SYT7 showed a reduction of about 50% of asynchronous release after individual stimuli and decreased short-term facilitation. In SYT3/7 double knockouts, asynchronous release was diminished by over 75% and facilitation was completely abolished in all types of synapses tested. An allosteric fusion model where different SYT isoforms cooperatively promote synaptic vesicles fusogenicity depending on their individual Ca 2+ -binding kinetics was capable of recapitulating both experimental findings well. Therefore, we postulate that short-term plasticity and asynchronous release are manifestations of the same mechanism – a transient increase in synaptic vesicle fusogenicity due to binding of multiple SYT molecules.

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