2019
DOI: 10.1016/j.cell.2019.09.011
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Neuromodulator Signaling Bidirectionally Controls Vesicle Numbers in Human Synapses

Abstract: Neuromodulators bind to pre-and postsynaptic G protein-coupled receptors (GPCRs), are able to quickly change intracellular cyclic AMP (cAMP) and Ca 2+ 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 t… Show more

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Cited by 76 publications
(64 citation statements)
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“…Disengagement of SVs from synaptic clusters 8 , 14 , 55 58 might provide a regulatory mechanism to control SV relocation by feeding extrasynaptic AT, thereby linking SV traffic to synaptic plasticity. We tested this hypothesis by activation of PKA, a well-studied intermediary of multiple neuromodulators, dopamine 59 , serotonin 60 , and brain-derived neurotrophic factor 61 , which influence synaptic plasticity.…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…Disengagement of SVs from synaptic clusters 8 , 14 , 55 58 might provide a regulatory mechanism to control SV relocation by feeding extrasynaptic AT, thereby linking SV traffic to synaptic plasticity. We tested this hypothesis by activation of PKA, a well-studied intermediary of multiple neuromodulators, dopamine 59 , serotonin 60 , and brain-derived neurotrophic factor 61 , which influence synaptic plasticity.…”
Section: Resultsmentioning
confidence: 99%
“…We tested this hypothesis by activation of PKA, a well-studied intermediary of multiple neuromodulators, dopamine 59 , serotonin 60 , and brain-derived neurotrophic factor 61 , which influence synaptic plasticity. Among many downstream actions, PKA can phosphorylate the vesicular adhesion molecule synapsin 1 62 – 64 , leading to dissociation of SVs with synapsin 1 from synaptic clusters and subsequent dispersion 58 , 65 67 , possibly by altering synapsin 1 liquid phases 57 . The deletion of synapsins greatly increases SV interbouton mobility seen as accelerated FRAP of synaptophysin-I:EGFP 68 .…”
Section: Resultsmentioning
confidence: 99%
“…The intrinsic upstream trigger for cAMP signaling at cholinergic synapses remains to be identified. Recently, neuromodulators were shown to affect synapsin phosphorylation after 30 min through cAMP pathways, and to alter SV numbers in murine and human neurons (Patzke et al, 2019). PKA inhibition increased, and cAMP upregulation decreased SV numbers.…”
Section: Discussionmentioning
confidence: 99%
“…In fact, vesicle clustering at the presynaptic terminal is known to be mediated by the synapsin family of proteins (Milovanovic et al, 2018;Pechstein et al, 2020) and synapsins contain a conserved PKA phosphorylation site (Serine9) (Czernik et al, 1987). PKA and synapsin mediated modulation of vesicle availability has been observed also in cultured human neurons (Patzke et al, 2019).…”
Section: Discussionmentioning
confidence: 99%
“…Forskolin-driven increase in cAMP concentration and the subsequent activation of PKA have recently been shown to act on synapsin to modulate short-term plasticity (Cheng et al, 2018), multivesicular release (Vaden et al, 2019), and vesicle availability (Patzke et al, 2019). We analyzed SV 3Ddistribution in the presynaptic mossy fiber bouton and compared the number and localization of SVs under forskolin and control conditions.…”
Section: Synaptic Vesicles Disperse Upon Potentiationmentioning
confidence: 99%