Neurotransmitter-Triggered Transfer of Exosomes Mediates Oligodendrocyte–Neuron Communication

Reciprocal interactions between neurons and oligodendrocytes are not only crucial for myelination, but also for long-term survival of axons. Degeneration of axons occurs in several human myelin diseases, however the molecular mechanisms of axon-glia communication maintaining axon integrity are poorly understood. Here, we describe the signal-mediated transfer of exosomes from oligodendrocytes to neurons. These endosome-derived vesicles are secreted by oligodendrocytes and carry specific protein and RNA cargo. We show that activity-dependent release of the neurotransmitter glutamate triggers oligodendroglial exosome secretion mediated by Ca2+ entry through oligodendroglial NMDA and AMPA receptors. In turn, neurons internalize the released exosomes by endocytosis. Injection of oligodendroglia-derived exosomes into the mouse brain results in functional retrieval of exosome cargo in neurons. Supply of cultured neurons with oligodendroglial exosomes improves neuronal viability under conditions of cell stress. These findings indicate that oligodendroglial exosomes participate in a novel mode of bidirectional neuron-glia communication contributing to neuronal integrity.

神经元与少突胶质细胞之间的双向相互作用，不仅对髓鞘形成至关重要，同时也是轴突长期存活的必要条件。多种人类髓鞘疾病中均会出现轴突变性，但目前学界对维持轴突完整性的轴突-胶质细胞通讯分子机制仍知之甚少。本研究报道了少突胶质细胞向神经元进行信号介导的外泌体（exosomes）转运现象：这类由内体衍生的囊泡由少突胶质细胞分泌，并携带有特定的蛋白质与RNA载荷。研究显示，神经递质谷氨酸的活性依赖性释放，可通过少突胶质细胞膜上的NMDA受体与AMPA受体介导的钙离子内流，触发少突胶质细胞外泌体的分泌。反之，神经元可通过内吞作用摄取这些释放出的外泌体。将少突胶质细胞来源的外泌体注入小鼠大脑后，可在神经元中实现外泌体载荷的功能性摄取。向体外培养的神经元添加少突胶质细胞来源的外泌体，可在细胞应激条件下提升神经元的存活率。上述研究结果表明，少突胶质细胞外泌体参与了一种全新的双向神经元-胶质细胞通讯模式，该模式对维持神经元完整性具有重要意义。