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Unc13A dynamically stabilizes vesicle priming at synaptic release sites for short-term facilitation and homeostatic potentiation

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  • Meida Jusyte, Leibniz Institute for Molecular Pharmacology, Charité – Universitätsmedizin Berlin
  • ,
  • Natalie Blaum, University of Copenhagen
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  • Mathias A. Böhme, Leibniz Institute for Molecular Pharmacology, Leipzig University
  • ,
  • Manon M.M. Berns, University of Copenhagen
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  • Alix E. Bonard, University of Copenhagen
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  • Ábel B. Vámosi, University of Copenhagen
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  • Kavya V. Pushpalatha, University of Copenhagen
  • ,
  • Janus R.L. Kobbersmed
  • Alexander M. Walter, Leibniz Institute for Molecular Pharmacology, Charité – Universitätsmedizin Berlin, University of Copenhagen

Presynaptic plasticity adjusts neurotransmitter (NT) liberation. Short-term facilitation (STF) tunes synapses to millisecond repetitive activation, while presynaptic homeostatic potentiation (PHP) of NT release stabilizes transmission over minutes. Despite different timescales of STF and PHP, our analysis of Drosophila neuromuscular junctions reveals functional overlap and shared molecular dependence on the release-site protein Unc13A. Mutating Unc13A's calmodulin binding domain (CaM-domain) increases baseline transmission while blocking STF and PHP. Mathematical modeling suggests that Ca2+/calmodulin/Unc13A interaction plastically stabilizes vesicle priming at release sites and that CaM-domain mutation causes constitutive stabilization, thereby blocking plasticity. Labeling the functionally essential Unc13A MUN domain reveals higher STED microscopy signals closer to release sites following CaM-domain mutation. Acute phorbol ester treatment similarly enhances NT release and blocks STF/PHP in synapses expressing wild-type Unc13A, while CaM-domain mutation occludes this, indicating common downstream effects. Thus, Unc13A regulatory domains integrate signals across timescales to switch release-site participation for synaptic plasticity.

Original languageEnglish
Article number112541
JournalCell Reports
Publication statusPublished - Jun 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors

    Research areas

  • CP: Neuroscience, neurotransmitter release sites, presynaptic homeostatic potentiation, short-term facilitation, synaptic plasticity, Unc13A

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