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Postsynaptic synucleins mediate endocannabinoid signaling (nature.com)
submitted 9d ago by Robert_Larsson
Robert_Larsson [OP] 3 points 9d ago
**Abstract**
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.
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.
Fragrant_Tip5499 3 points 6d ago
Who knew synucleins had a hidden talent for endocannabinoid release? They sure like to surprise us!
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Fidelroyolanda12 1 points 7d ago
What is the significance of this?
Robert_Larsson [OP] 1 points 7d ago
Depends on if you're interested in cannabinoid MoA and why they seem to regulate excitability more than inhibition.
Fidelroyolanda12 1 points 7d ago
Seems interesting, I'll have a look
Dieg_1990 1 points 7d ago
Statistically significant, otherwise they would have struggled to publish
Fidelroyolanda12 1 points 7d ago
I meant it more like "why is this important"
Dieg_1990 3 points 6d ago
Because the endocannabinoid system is one of the main regulators of neuronal transmission and a fundamental player for brain homeostasis. Up until now, nobody had proved how the endocannabinoids moved retrogradely tho and everyone assumed they just diffused. Discovering new members of this system can lead to novel therapies for treating an array of disorders
Acetylcholine 2 points 5d ago
I think beyond that, alpha synuclein is an incredibly abundant protein in the brain, it is a major player in the pathogenesis of parkinson's disease, and people have been trying to nail down what it does for decades with little success. There's been a handful of papers trying over the years but this is probably the most concrete synaptic phenotype shown thus far.
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