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Munc13-1 is a Ca2+-phospholipid-dependent vesicle priming hub that shapes synaptic short-term plasticity and enables sustained neurotransmission

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Lipstein,  N.
Molecular neurobiology, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons14934

Chang,  S.
Molecular neurobiology, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons276637

Lopez-Murcia,  F. J.
Molecular neurobiology, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons185565

Taschenberger,  H.
Molecular neurobiology, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182104

Brose,  N.
Molecular neurobiology, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Citation

Lipstein, N., Chang, S., Lin, K.-H., Lopez-Murcia, F. J., Neher, E., Taschenberger, H., et al. (2021). Munc13-1 is a Ca2+-phospholipid-dependent vesicle priming hub that shapes synaptic short-term plasticity and enables sustained neurotransmission. Neuron, 109, 3980-4000.e7. doi:10.1016/j.neuron.2021.09.054.


Cite as: https://hdl.handle.net/21.11116/0000-000A-CE86-7
Abstract
During ongoing presynaptic action potential (AP) firing, transmitter release is limited by the availability of
release-ready synaptic vesicles (SVs). The rate of SV recruitment (SVR) to release sites is strongly upregu-
lated at high AP frequencies to balance SV consumption. We show that Munc13-1—an essential SV priming
protein—regulates SVR via a Ca2+-phospholipid-dependent mechanism. Using knockin mouse lines with
point mutations in the Ca2+-phospholipid-binding C2B domain of Munc13-1, we demonstrate that abolishing
Ca2+-phospholipid binding increases synaptic depression, slows recovery of synaptic strength after SV pool
depletion, and reduces temporal fidelity of synaptic transmission, while increased Ca2+-phospholipid binding
has the opposite effects. Thus, Ca2+-phospholipid binding to the Munc13-1-C2B domain accelerates SVR,
reduces short-term synaptic depression, and increases the endurance and temporal fidelity of neurotrans-
mission, demonstrating that Munc13-1 is a core vesicle priming hub that adjusts SV re-supply to demand.