Unc13A dynamically stabilizes vesicle priming at synaptic release sites for short-term facilitation and homeostatic potentiation
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Unc13A dynamically stabilizes vesicle priming at synaptic release sites for short-term facilitation and homeostatic potentiation. / Jusyte, Meida; Blaum, Natalie; Böhme, Mathias A.; Berns, Manon M.M.; Bonard, Alix E.; Vámosi, Ábel B.; Pushpalatha, Kavya V.; Kobbersmed, Janus R.L.; Walter, Alexander M.
In: Cell Reports, Vol. 42, No. 6, 112541, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Unc13A dynamically stabilizes vesicle priming at synaptic release sites for short-term facilitation and homeostatic potentiation
AU - Jusyte, Meida
AU - Blaum, Natalie
AU - Böhme, Mathias A.
AU - Berns, Manon M.M.
AU - Bonard, Alix E.
AU - Vámosi, Ábel B.
AU - Pushpalatha, Kavya V.
AU - Kobbersmed, Janus R.L.
AU - Walter, Alexander M.
N1 - Publisher Copyright: © 2023 The Authors
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - CP: Neuroscience
KW - neurotransmitter release sites
KW - presynaptic homeostatic potentiation
KW - short-term facilitation
KW - synaptic plasticity
KW - Unc13A
U2 - 10.1016/j.celrep.2023.112541
DO - 10.1016/j.celrep.2023.112541
M3 - Journal article
C2 - 37243591
AN - SCOPUS:85160063014
VL - 42
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 6
M1 - 112541
ER -
ID: 348164015