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.

内源性大麻素是整个神经系统突触传递最强大的调节剂之一，但人们对内源性大麻素从突触后区室的释放知之甚少。在这里，我们报告了一个意外的发现，即内源性大麻素的释放需要突触核蛋白，这是帕金森病的关键因素。我们发现内源性大麻素通过突触核蛋白依赖性和 SNARE 依赖性机制在突触后释放。具体来说，我们发现突触核蛋白缺失会阻碍内源性大麻素依赖性突触可塑性；该阻断可通过野生型突触后表达而逆转，但突变型 α-突触核蛋白则不会。全细胞记录和内源性大麻素信号传导的直接光学监测表明，突触核蛋白缺失特异性地阻止了内源性大麻素的释放。鉴于突触核蛋白在调节囊泡生命周期中的突触前作用，我们假设内源性大麻素通过膜相互作用机制释放。与这一假设一致，破伤风毒素轻链的突触后表达（可裂解突触短蛋白 SNARE）也会阻断内源性大麻素依赖性信号传导。内源性大麻素通过突触核蛋白依赖性机制释放的意外发现与突触核蛋白在膜运输中的一般功能一致，并为神经元如何释放内源性大麻素以诱导突触可塑性的长期谜团增加了一部分。