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Cell. 2019 Oct 3;179(2):498-513.e22. doi: 10.1016/j.cell.2019.09.011.

Neuromodulator Signaling Bidirectionally Controls Vesicle Numbers in Human Synapses.

Author information

1
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA. Electronic address: patzke@stanford.edu.
2
Institut für Neurophysiologie, Charité Universitätsmedizin, 10117 Berlin, Germany.
3
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
4
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.

Abstract

Neuromodulators bind to pre- and postsynaptic G protein-coupled receptors (GPCRs), are able to quickly change intracellular cyclic AMP (cAMP) and Ca2+ levels, and are thought to play important roles in neuropsychiatric and neurodegenerative diseases. Here, we discovered in human neurons an unanticipated presynaptic mechanism that acutely changes synaptic ultrastructure and regulates synaptic communication. Activation of neuromodulator receptors bidirectionally controlled synaptic vesicle numbers within nerve terminals. This control correlated with changes in the levels of cAMP-dependent protein kinase A-mediated phosphorylation of synapsin-1. Using a conditional deletion approach, we reveal that the neuromodulator-induced control of synaptic vesicle numbers was largely dependent on synapsin-1. We propose a mechanism whereby non-phosphorylated synapsin-1 "latches" synaptic vesicles to presynaptic clusters at the active zone. cAMP-dependent phosphorylation of synapsin-1 then removes the vesicles. cAMP-independent dephosphorylation of synapsin-1 in turn recruits vesicles. Synapsin-1 thereby bidirectionally regulates synaptic vesicle numbers and modifies presynaptic neurotransmitter release as an effector of neuromodulator signaling in human neurons.

KEYWORDS:

cAMP; guanfacine; high-pressure freeze EM; human synapse; neuromodulator; norepinephrine; old human neurons; serotonin; synapsin-1; synaptic vesicles

PMID:
31585084
DOI:
10.1016/j.cell.2019.09.011

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