Postsynaptic synucleins mediate endocannabinoid signaling.
Journal
Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
received:
19
01
2023
accepted:
21
04
2023
medline:
8
6
2023
pubmed:
30
5
2023
entrez:
29
5
2023
Statut:
ppublish
Résumé
Endocannabinoids are among the most powerful modulators of synaptic transmission throughout the nervous system, and yet little is understood about the release of endocannabinoids from postsynaptic compartments. Here we report an unexpected finding that endocannabinoid release requires synucleins, key contributors to Parkinson's disease. We show that endocannabinoids are released postsynaptically by a synuclein-dependent and SNARE-dependent mechanism. Specifically, we found that synuclein deletion blocks endocannabinoid-dependent synaptic plasticity; this block is reversed by postsynaptic expression of wild-type but not of mutant α-synuclein. Whole-cell recordings and direct optical monitoring of endocannabinoid signaling suggest that the synuclein deletion specifically blocks endocannabinoid release. Given the presynaptic role of synucleins in regulating vesicle lifecycle, we hypothesize that endocannabinoids are released via a membrane interaction mechanism. Consistent with this hypothesis, postsynaptic expression of tetanus toxin light chain, which cleaves synaptobrevin SNAREs, also blocks endocannabinoid-dependent signaling. The unexpected finding that endocannabinoids are released via a synuclein-dependent mechanism is consistent with a general function of synucleins in membrane trafficking and adds a piece to the longstanding puzzle of how neurons release endocannabinoids to induce synaptic plasticity.
Identifiants
pubmed: 37248337
doi: 10.1038/s41593-023-01345-0
pii: 10.1038/s41593-023-01345-0
pmc: PMC10244176
doi:
Substances chimiques
Endocannabinoids
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
997-1007Subventions
Organisme : NINDS NIH HHS
ID : P50 NS094733
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH052804
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS091144
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS103037
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS113358
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Informations de copyright
© 2023. The Author(s).
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