Cannabis and cannabinoid drugs are central agents that are used widely recreationally and are employed broadly for treating psychiatric conditions. Cannabinoids primarily act by stimulating presynaptic CB1 receptors (CB1Rs), the most abundant G-protein-coupled receptors in brain. CB1R activation decreases neurotransmitter release by inhibiting presynaptic Ca2+ channels and induces long-term plasticity by decreasing cellular cAMP levels. Here we identified an unanticipated additional mechanism of acute cannabinoid signaling in presynaptic terminals that regulates the size of synaptic vesicle pools available for neurotransmitter release. Specifically, we show that activation of CB1Rs in human and mouse neurons rapidly recruits vesicles to nerve terminals by suppressing the cAMP-dependent phosphorylation of synapsins. We confirmed this unanticipated mechanism using conditional deletion of synapsin-1, the predominant synapsin isoform in human neurons, demonstrating that synapsin-1 significantly contributes to the CB1R-dependent regulation of neurotransmission. Interestingly, acute activation of the Gi-DREADD hM4D mimics the effect of CB1R activation in a synapsin-1-dependent manner, suggesting that the control of synaptic vesicle numbers by synapsin-1 phosphorylation is a general presynaptic mechanism of neuromodulation. Thus, we uncovered a CB1R-dependent presynaptic mechanism that rapidly regulates the organization and neurotransmitter release properties of synapses.
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This work was supported by grants from the NIH (MH092931 and AG010770 to TCS), from the German Research Council (DFG PA 2110/1-1 to CP), and the DFG Reinhart Koselleck Project and SFB958 (to CR). We thank Drs Louise Giam and Xiao Du for sharing their unpublished RNA-sequencing data, Dr Sean Aric Merrill for helping with STORM microscopy, Dr Amber Nabet and Sofia Essayan-Perez for advice.
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Patzke, C., Dai, J., Brockmann, M.M. et al. Cannabinoid receptor activation acutely increases synaptic vesicle numbers by activating synapsins in human synapses. Mol Psychiatry 26, 6253–6268 (2021). https://doi.org/10.1038/s41380-021-01095-0