biostudies-literatureUnknownMehta NNIMH NIH HHSNHGRI NIH HHSNINDS NIH HHSSynaptic plasticity is crucial for learning and memory. The presynaptic calcium sensor synaptotagmin 7 (syt7) regulates aspects of short-term plasticity (STP), but the underlying mechanisms remain unclear. Here, we show that alternative splicing of the syt7 juxtamembrane linker acts as a molecular switch at both biochemical and functional levels. The α and β variants undergo liquid-liquid phase separation to form condensates, while the γ variant forms aggregates. Using iGluSnFR imaging, we found that when expressed at equal levels, these three isoforms also diverge regarding their abilities to regulate two key aspects of STP: paired-pulse facilitation and synaptic depression. Further, MINFLUX super resolution microscopy demonstrated that syt7 forms clusters in the active zone, well-positioned to directly control synaptic vesicle dynamics. Thus, alternative splicing might fine-tune STP by differentially impacting syt7 oligomerization.bioRxiv : the preprint server for biology2025.10.27.684894https://www.ebi.ac.uk/biostudies/studies/S-EPMC12636619biostudies-literatureAlternative splicing of synaptotagmin 7 regulates oligomerization and short-term synaptic plasticity.PMC12636619UM1 HG006348R35 NS136306R01 MH061876Mehta NJain ASalaka RJSubramani SMishra SWozney MChapman ERLarson DTKaur SfalseAlternative splicing of synaptotagmin 7 regulates oligomerization and short-term synaptic plasticity.Synaptic plasticity is crucial for learning and memory. The presynaptic calcium sensor synaptotagmin 7 (syt7) regulates aspects of short-term plasticity (STP), but the underlying mechanisms remain unclear. Here, we show that alternative splicing of the syt7 juxtamembrane linker acts as a molecular switch at both biochemical and functional levels. The α and β variants undergo liquid-liquid phase separation to form condensates, while the γ variant forms aggregates. Using iGluSnFR imaging, we found that when expressed at equal levels, these three isoforms also diverge regarding their abilities to regulate two key aspects of STP: paired-pulse facilitation and synaptic depression. Further, MINFLUX super resolution microscopy demonstrated that syt7 forms clusters in the active zone, well-positioned to directly control synaptic vesicle dynamics. Thus, alternative splicing might fine-tune STP by differentially impacting syt7 oligomerization.2025-01-01T00:00:00Z2025 Oct2026-06-02T03:11:08.447Z2026-06-02T03:09:05.245ZS-EPMC126366194127874610.1101/2025.10.27.684894