Unc13A dynamically stabilizes vesicle priming at synaptic release sites for short-term facilitation and homeostatic potentiation
Meida Jusyte,
Natalie Blaum,
Mathias A. Böhme,
Manon M.M. Berns,
Alix E. Bonard,
Ábel B. Vámosi,
Kavya V. Pushpalatha,
Janus R.L. Kobbersmed,
Alexander M. Walter
Affiliations
Meida Jusyte
Molecular and Theoretical Neuroscience, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany; Einstein Center for Neurosciences Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany
Natalie Blaum
Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark
Mathias A. Böhme
Molecular and Theoretical Neuroscience, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany; Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Leipzig, Germany
Manon M.M. Berns
Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark
Alix E. Bonard
Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark
Ábel B. Vámosi
Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark
Kavya V. Pushpalatha
Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark
Janus R.L. Kobbersmed
Department of Mathematical Sciences, University of Copenhagen, Copenhagen, Denmark; Center of Functionally Integrative Neuroscience, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
Alexander M. Walter
Molecular and Theoretical Neuroscience, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany; Einstein Center for Neurosciences Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany; Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark; Corresponding author
Summary: 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.
